Lipid droplet–mitochondria contact sites as druggable spatial-pharmacology targets in respiratory disease: cross–cell-type mechanisms and translational strategies

Abstract

Lipid droplets and mitochondria form regulated contact sites whose molecular composition, phosphorylation state and spatial geometry now behave as measurable, druggable variables in living cells. The molecular toolkit has been mapped in liver, muscle and adipose tissue, yet its application to respiratory disease has lagged despite a lung-specific dependence on lipid biology that spans surfactant biogenesis, alveolar-macrophage lipid handling and fibroblast-driven remodelling. This review argues that the lipid-droplet–mitochondria contact site is an emerging spatial-pharmacology target in respiratory medicine, and organises the evidence into a three-way matrix with explicit grading of direct, indirect and cross-tissue evidence. A common molecular toolkit built around perilipin-family scaffolds, mitochondrial-outer-membrane tethers, an endoplasmic-reticulum bridging apparatus and the PFKL–PLIN2–CPT1A flux node (mechanistically established in hepatocellular carcinoma and inferred in lung) is rewired into cell-type-specific configurations across alveolar type 2 cells, macrophages, fibroblasts, endothelium and lung adenocarcinoma. That toolkit acquires a distinct disease role across idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, tuberculosis, severe acute respiratory syndrome coronavirus two infection and lung cancer, generating a matrix of cell-type-by-disease configurations that no prior review has systematized. Four target axes, namely, tether occupancy, lipid flux, redox coupling and cell-type-precise delivery, converge geometrically at the interface and motivate combination strategies rather than pan-mitochondrial single-agent approaches. Inhaled lipid nanoparticles, mucus-penetrating carriers and engineered extracellular vesicles bring these targets within reach with cell-type precision. Endothelial contact-site biology is identified as the largest evidence gap and discussed candidly. The framework is offered as a roadmap for tether-axis compound development, contact-site engagement biomarkers and dual-axis inhaled therapeutics.

1 Introduction

Lipid droplets were long treated as inert depots. Three decades of cell biology have replaced that view with one of a dynamic organelle whose contacts with mitochondria can now be measured directly. Functional segregation experiments first showed that lipid-droplet–tethered mitochondria are biochemically distinguishable from the cytoplasmic pool, with enhanced pyruvate-driven respiration and a discrete bioenergetic role in fat storage (Benador et al., 2018). Subsequent work in liver established that peridroplet mitochondria carry higher pACC2, MFN2, and CPT1 activity than their cytoplasmic counterparts, anchoring the functional-segregation concept in vivo (Talari et al., 2023). Distinct dynamic regimes have been recognised at this interface. Lipid droplets and mitochondria establish a kiss-and-run pattern in cells with high lipolytic flux and an anchored, stable pattern in oxidative tissues, with the anchored configuration becoming more prevalent during brown and beige adipocyte differentiation (Cui and Liu, 2020). Proximity-proteomic dissection has since converted these observations into a defined molecular interface. An ESYT1/ESYT2–VAPB tripartite assembly was mapped at the lipid-droplet–mitochondria–endoplasmic reticulum junction, and its disruption reduced droplet-derived fatty-acid oxidation and altered tricarboxylic-acid intermediates in cells and mice (Bezawork-Geleta et al., 2025). A separate proximity-labelling effort in muscle-derived cells identified an interaction between PLIN5 and the long-chain acyl-CoA synthetase FATP4 that drives fatty-acid channelling from droplet to mitochondrion during starvation (Miner et al., 2023). A complementary line of work identified PLIN5 phosphorylation at serine 155 as a switch-like, quantitative regulator of contact-site abundance and lipid flux through the interface (Kang et al., 2026; Kien et al., 2022; Zhang et al., 2022; Griseti et al., 2024), consistent with parallel post-translational regulators of droplet–mitochondria coupling (Niu et al., 2025). The accompanying News and Views framed PLIN5-S155 as an early-stage indicator of contact-site dysfunction in metabolic-dysfunction-associated steatotic liver disease (Segalé et al., 2026). A connected line of work in adipocytes had earlier defined MIGA2 as a triple-organelle anchor that ties mitochondria to the endoplasmic reticulum and to lipid droplets and is required for efficient lipid storage, providing an additional anatomical scaffold for the contact-site concept (Freyre et al., 2019; Bórquez et al.; Peng et al., 2026). Together these advances have moved the lipid-droplet–mitochondria contact site (LDMC) from descriptive ultrastructure into the territory of mechanistically tractable, pharmacologically addressable biology (Klein et al., 2021; Herker et al., 2021; Wu et al., 2022; Zadoorian et al., 2023), with recent mechanistic refinements consolidating this view (Zhang et al., 2024; Smolk et al., 2025).

The case for treating LDMC as a respiratory-disease target rests on the lung’s unusual lipid economy. The alveolar surface depends on a continuous supply of saturated phospholipid for surfactant, manufactured by alveolar type 2 cells and packaged in lamellar bodies, lysosome-related organelles that are distinct from cytoplasmic lipid droplets but whose biogenesis is coupled to mitochondrial metabolism (Xu et al., 2023; Cañadas et al., 2020; Pranty et al., 2026). Surfactant homeostasis is also coupled to mitochondrial function. GCN5L1, a mitochondrial acetyltransferase regulator, controls lamellar-body biogenesis and trafficking in alveolar epithelial cells, linking mitochondrial acetyl-coenzyme A flux to surfactant assembly (Zhu Y. et al., 2024; Dietl and Frick, 2021; Li et al., 2022). Surfactant is reclaimed and recycled by alveolar macrophages, and dysregulation of this loop produces foam-cell–dominated injury patterns seen in chronic obstructive pulmonary disease, tuberculosis, and silicosis (Angeles-Lopez et al., 2025; Xie et al., 2025; Agarwal et al., 2021; Aloe et al., 2022). Activated lung fibroblasts add a second demand. Collagen deposition imposes a sustained requirement for mitochondrial acetyl-coenzyme A and obligates β-oxidation, and the lung progenitor plasticity needed for aberrant repair in idiopathic pulmonary fibrosis depends on fatty-acid oxidation that is itself sensitive to droplet–mitochondria flux (Han et al., 2023; Bueno et al., 2020; Tian et al., 2023). Lung adenocarcinoma adds a third demand. Spatial mapping of mitochondrial networks in non–small cell lung cancer revealed that tumours with high oxidative phosphorylation organise peridroplet mitochondrial compartments that surround and contact lipid droplets, supplying a tumour-specific bioenergetic niche, while tumours with low oxidative phosphorylation displace the network into a perinuclear configuration with remodelled cristae (Fan and Tan, 2024; Jin and Yuan, 2020; Liu et al., 2023). Each of these lung-specific pressures recruits the same molecular machinery into cell-type-specific configurations, and each invites cell-type-resolved therapeutic targeting.

The current review landscape leaves this niche unfilled. Reviews of the LDMC interface synthesise data from liver, muscle, and adipose (Fan and Tan, 2024; Wang G. et al., 2025; Enkler and Spang, 2024), without organising them around lung cell types (Herker et al., 2021; Zhang et al., 2024; Smolk et al., 2025). Reviews of lung mitochondria focus on bioenergetic dysfunction in chronic lung disease but rarely integrate contact-site mechanisms with the tether catalogue (Cloonan et al., 2020; Pokharel et al., 2024). Reviews of lung lipid pathology cover foam-cell biology and surfactant homeostasis without engaging the tether and flux machinery in mechanistic detail (Agudelo et al., 2020; Najt et al., 2020). The present synthesis is built around the proposition that the LDMC interface, when read across alveolar type 2 cells, alveolar and interstitial macrophages, fibroblasts, endothelium, and lung adenocarcinoma cells, becomes a coherent, spatial-pharmacology target class in respiratory disease, with the caveat that most lung evidence remains indirect. The contact site is approachable by inhaled lipid nanoparticles and engineered extracellular vesicles, which together open a route to cell-type-precise intervention. The following argument first establishes the LDMC molecular toolkit and its recruiting pulmonary lipid economy. It then applies this toolkit across principal lung cell types. These include alveolar type 2 cells, alveolar and interstitial macrophages, fibroblasts, the pulmonary endothelium, and lung adenocarcinoma cells. This step distinguishes solid mechanisms from provisional ones. The resulting insights converge into a disease matrix. This matrix links idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, silicosis, acute respiratory distress syndrome, tuberculosis, severe acute respiratory syndrome coronavirus two infection, and lung adenocarcinoma to specific LDMC failure modes and cell-type entry points. Throughout, the endothelial layer is acknowledged as the most poorly resolved compartment. The discussion is deliberately structured to make this gap visible rather than concealed.

2 The LDMC interface across the lung

2.1 The molecular toolkit and the pulmonary lipid economy

2.1.1 A layered molecular interface

The LDMC interface is built from a small but structurally distinguishable set of perilipins, mitochondrial-outer-membrane anchors, endoplasmic-reticulum–coupled tethers, glycolytic adaptors, and lipid-transfer components. This toolkit, catalogued in liver, skeletal muscle, and adipose, can be read as a layered architecture rather than a list. Three structural classes can be defined. The first comprises droplet-side perilipins and their phosphorylation-regulated interactors. The second comprises mitochondrial-outer-membrane and endoplasmic-reticulum–anchored tethers that establish the physical contact. The third comprises adaptors and lipid-transfer modules that link contact-site occupancy to substrate flux. This organisation matters for the cell-type analyses below, because each lung cell type recruits these classes in characteristic combinations.

Perilipin-family proteins furnish the LDMC’s droplet-side interface. PLIN5 is the most extensively dissected member. Beyond its scaffolding of adipose triglyceride lipase (ATGL) and its co-activator CGI-58 at the droplet surface, PLIN5 docks long-chain fatty acids onto the long-chain acyl-coenzyme A synthetase FATP4 at droplet–mitochondria junctions, channelling fatty acids directly from droplet to mitochondrion during starvation rather than allowing them to enter the bulk cytoplasmic pool (Miner et al., 2023; Kien et al., 2022; Smolk et al., 2025). A separate function for PLIN5 has been resolved in muscle, where lipid-droplet–derived monounsaturated fatty acids traffic via PLIN5 to the nuclear deacetylase SIRT1 and allosterically activate it, coupling mobilised acyl chains to a downstream transcriptional programme (Zhang et al., 2022; Griseti et al., 2024; Najt et al., 2020). Quantitative control of contact-site abundance is exerted by phosphorylation. The phosphomimetic PLIN5-S155E variant collapses droplet–mitochondria coupling, whereas the phospho-deficient S155A variant amplifies it, expanding droplets and reducing lipotoxicity under a Western diet (Kang et al., 2026; Zhang et al., 2022; Niu et al., 2025). PLIN2 covers droplets in cells that do not strongly express PLIN5, including most non-oxidative epithelial cells, and is recruited to the LDMC by phosphorylation events that engage the glycolytic adaptor described below (Griseti et al., 2024; Zadoorian et al., 2023; Wang et al., 2020; Stephens and Johnson, 2025).

A second class of LDMC components is built from mitochondrial-outer-membrane and endoplasmic-reticulum–anchored tethers. Mitofusin 2 (MFN2) acts both as a fusion-promoting GTPase and as a heterotypic tether that, in adipose tissue, binds the lipid-droplet–localised heat-shock cognate Hsc70 to position mitochondria adjacent to droplets (Bórquez et al.; Fan and Tan, 2024). MIGA2, also known as mitoguardin-2, is anchored in the outer mitochondrial membrane and links mitochondria simultaneously to lipid droplets and to the endoplasmic reticulum, providing a triple-organelle scaffold that is required for efficient neutral-lipid storage (Freyre et al., 2019; Peng et al., 2026). A structural study has further resolved how the cytoplasmic lipid-transfer domain of MIGA2 binds phosphatidic acid and phosphatidylglycerol and reaches across the contact interface to support inter-organelle lipid transport at endoplasmic-reticulum–mitochondrion contact sites (Kim et al., 2022). A complementary endoplasmic-reticulum–bridged tether is provided by the extended synaptotagmins ESYT1 and ESYT2, which assemble with VAPB at a lipid-droplet–mitochondria–endoplasmic-reticulum tripartite junction whose disruption reduces droplet-derived fatty-acid oxidation, depletes tricarboxylic-acid intermediates, and causes lipotoxic stress in cells and in Esyt1/Esyt2-deficient mice (Bezawork-Geleta et al., 2025). Trafficking factors expand this layer. SNAP23 has been implicated in coupling droplet–mitochondria fusion-like events to fatty-acid mobilisation, and Rab8a, after phosphorylation by AMP-activated protein kinase, binds PLIN5 to recruit ATGL and accelerate droplet-to-mitochondrion fatty-acid flow, an axis catalogued across recent integrative reviews (Fan and Tan, 2024; Wang G. et al., 2025).

The third class translates contact-site occupancy into substrate flux. The glycolytic enzyme phosphofructokinase-liver (PFKL) phosphorylates PLIN2 under energetic stress, enabling PLIN2 to recruit the rate-limiting fatty-acid-import enzyme carnitine palmitoyltransferase 1A (CPT1A) to the droplet–mitochondria interface, thereby tightening tethering and amplifying β-oxidation. This mechanism was established in hepatocellular carcinoma, where PFKL- and PLIN2-phosphorylation levels track poor prognosis; it has not yet been demonstrated in lung tissue (Zhang et al., 2024; Smolk et al., 2025; Meng et al., 2024). This PFKL–PLIN2–CPT1A axis ties cytosolic glycolytic flux directly to droplet-derived oxidative output through the contact site and represents one of the most pharmacologically addressable elements of the LDMC toolkit. Lipid-transfer is also assisted at the droplet side by acyl-coenzyme A synthetase long-chain family members, which channel activated acyl chains into mitochondrial CPT1A loading.

Imaging now resolves the LDMC at near-molecular precision. Cryogenic correlative light and electron microscopy of alveolar type 2 cells has reconstructed lamellar-body membrane architecture and its juxtaposition with mitochondria (Klein et al., 2021). Because lamellar bodies are lysosome-related organelles rather than lipid droplets, this juxtaposition templates a distinct lamellar-body–mitochondria interaction, not an LDMC in the strict sense (Section 2.1.2). Live-cell and super-resolution approaches such as lattice light-sheet microscopy capture the kiss-and-run versus anchored dynamic regimes at physiologically relevant time scales, and focused-ion-beam scanning electron microscopy resolves the three-dimensional anchor geometry. Together, these tools permit quantitative read-outs of contact-site abundance and dynamics that could, in principle, translate into pharmacological end points. The druggability of individual LDMC components varies widely and remains largely prospective. PLIN5-S155 phosphorylation is reversible and downstream of established kinases, making it a candidate for indirect pharmacological control; MFN2 has small-molecule activators in preclinical development; MIGA2 lipid binding may be tractable through fragment-based screening once a structural compound library becomes available; and CPT1A is targeted by preclinical tool inhibitors such as etomoxir, whose dose-dependent off-target effects preclude clinical use (Section 3.1). The layered LDMC architecture and its druggable nodes are summarised as a molecular schematic in Figure 1 and catalogued component-by-component in Table 1. Cell-type-specific tether stoichiometries in alveolar type 2 cells, alveolar and interstitial macrophages, lung fibroblasts, and pulmonary endothelium have not been systematised at the level of detail now available for liver and skeletal muscle, and this gap is engaged below.

FIGURE 1

Because the evidence base behind this toolkit is uneven, we grade every mechanism discussed in this review into three tiers and signal the tier wherever a claim is made. Tier (i) comprises direct lung LDMC evidence: structural or functional data that resolve lipid-droplet–mitochondria contacts in lung cells or tissue, currently limited to spatial-proteomic mapping of peridroplet mitochondria in non–small cell lung cancer (Han et al., 2023; Jin and Yuan, 2020; Liu et al., 2023). Cryogenic correlative light and electron microscopy of lamellar-body–mitochondria juxtaposition in alveolar type 2 cells (Klein et al., 2021) is not classified as Tier (i) LDMC evidence, because lamellar bodies are lysosome-related organelles rather than cytoplasmic lipid droplets; we treat that juxtaposition as a distinct organelle interaction and grade it as Tier (ii) (Section 2.1.2). Tier (ii) comprises indirect lung evidence: metabolic, transcriptomic, genetic or pharmacological data from lung systems that implicate LDMC components without resolving the contact site itself; the majority of the lung literature, including the MFN1/MFN2, HMGCS2, CPT1A–Bcl-2 and GCN5L1 axes, sits here. Tier (iii) comprises cross-tissue analogy: mechanisms established in liver, muscle or adipose including the PLIN5-S155 phospho-switch, MIGA2 triple-organelle anchoring, ESYT1/2–VAPB tripartite tethering and the PFKL–PLIN2–CPT1A axis, whose operation in lung cells is inferred rather than demonstrated. This grading is carried through the text, Tables 2, 3 and the figures.

2.1.2 Three pulmonary lipid demands that recruit the toolkit

The lung imposes three lipid demands that few other organs combine in a single tissue. Surfactant phospholipid must be manufactured and secreted on a sustained basis, recycled and re-secreted by alveolar phagocytes, and metered into a tightly regulated mucociliary–alveolar interface. Each of these tracks depends on lipid-handling organelles whose biogenesis and trafficking are coupled to mitochondrial metabolism, and each is mitochondrion-coupled in ways that map onto the LDMC toolkit with varying degrees of directness.

Surfactant biogenesis begins in alveolar type 2 cells. Saturated phosphatidylcholines, most notably dipalmitoylphosphatidylcholine, are synthesised through the cytidine-diphosphate–choline pathway and packaged into lamellar bodies, lysosome-related organelles that exhibit a multilamellar architecture defined by recent cryogenic electron tomography (Klein et al., 2021; Cañadas et al., 2020; Pranty et al., 2026). Lamellar-body biogenesis is mitochondrion-coupled. The mitochondrial-acetyltransferase regulator GCN5L1 controls lamellar-body assembly and intracellular trafficking in alveolar epithelial cells, linking acetyl-coenzyme A flux to surfactant packaging (Xu et al., 2023; Pranty et al., 2026; Dietl and Frick, 2021; Li et al., 2022). Lamellar bodies are nevertheless lysosome-related organelles, biogenetically and compositionally distinct from cytoplasmic lipid droplets. The GCN5L1-dependent coupling of lamellar-body biogenesis to mitochondrial acetyl-coenzyme A flux is therefore best described as a distinct lamellar-body–mitochondria interaction rather than an LDMC in the strict sense, and throughout this review we treat it as such while noting where the two organelle systems share regulatory machinery.

After secretion into the alveolar lumen, the surfactant pool is reclaimed by alveolar macrophages and recycled. This loop demands sustained lysosomal–mitochondrial coordination, and its disruption is now recognised as a unifying axis across chronic obstructive pulmonary disease, tuberculosis, and silicosis, in which surfactant components accumulate in injury-associated macrophages and shape a foam-cell phenotype that supports persistent inflammation in COPD-, silicosis-, and TB-associated foam-cell phenotypes (Zhu Y. et al., 2024; Xie et al., 2025; Agudelo et al., 2020) and adjacent macrophage-driven inflammatory states (Agarwal et al., 2021; Aloe et al., 2022; Adamcakova and Mokra, 2021). The same loop is hijacked by viral infection. Severe acute respiratory syndrome coronavirus 2 ORF3a reprograms host lipid metabolism by inducing microlipophagy, expanding lipid-droplet reserves and remodelling perinuclear membranes to support replication-organelle biogenesis (Li Z. et al., 2025; Dias et al., 2020; Wang et al., 2023; López-Ayllón et al., 2024). These observations show that the surfactant-recycling loop is not a passive housekeeping function but a metabolically active LDMC-adjacent compartment that disease processes can rewire.

A second lung-specific demand arises from collagen-producing fibroblasts. Aberrant repair in idiopathic pulmonary fibrosis depends on lung-progenitor plasticity that is itself sustained by fatty-acid oxidation, and conditional impairment of this pathway reorganises alveolar regeneration (Angeles-Lopez et al., 2025; Bueno et al., 2020; Tian et al., 2023). Mechanistically, collagen synthesis is a sustained acetyl-coenzyme A sink, and droplet-derived fatty acids channelled through the LDMC interface help meet that demand without committing the cell to lipotoxic free-fatty-acid exposure. The third demand is supplied by tumour cells. Spatial mapping of mitochondrial networks in non–small cell lung cancer has shown that oxidative-phosphorylation-high tumours organise peridroplet mitochondrial compartments that physically contact lipid droplets and sustain a tumour-specific bioenergetic niche, whereas oxidative-phosphorylation-low tumours displace the mitochondrial network into a perinuclear configuration with remodelled cristae (Han et al., 2023; Jin and Yuan, 2020; Liu et al., 2023; Zhang et al., 2025). This finding extends the peridroplet concept beyond brown adipocytes and hepatocytes into a clinically relevant lung context.

Across these three demands, related molecular machinery is recruited into cell-type-specific configurations. In the secretory limb, lamellar-body–mitochondria coupling (a distinct organelle interaction; Section 2.1.2) organises surfactant assembly, foam-macrophage cholesterol metabolism couples LDMC remodelling to surfactant uptake and turnover, fibroblast fatty-acid oxidation meets a collagen-synthesis demand through PLIN5–FATP4-like channelling inferred from other tissues, and tumour peridroplet mitochondria reuse the anchored configuration described for brown adipocytes. The following subsections take up each cell type in turn; Figure 2 provides a cell-type-resolved overview and Table 2 summarises the dominant LDMC configuration, molecular components and evidence strength for each compartment.

FIGURE 2

2.2 Cell-type rewiring across the lung

2.2.1 Alveolar type 2 cells: surfactant economy meets fibrotic vulnerability

Alveolar type 2 cells are the lung’s lipid-packaging specialists. They synthesise and secrete surfactant phospholipid, mediate alveolar repair, and contain lamellar bodies, lysosome-related organelles that are distinct from cytoplasmic lipid droplets but whose biogenesis is tightly coupled to mitochondrial metabolism. Mitochondrial coupling in alveolar type 2 cells is consequently both a physiological device for surfactant economy and a vulnerability that converges on idiopathic pulmonary fibrosis (IPF) and acute respiratory distress syndrome.

Mitochondrial fusion is the most clearly resolved mechanistic axis. Conditional deletion of the outer-membrane GTPases MFN1 and MFN2 in murine alveolar type 2 cells causes morbidity, mortality, and spontaneous lung fibrosis, and disables the synthesis of surfactant phospholipids and cholesterol; fatty-acid-synthase deficiency in the same cells phenocopies and exacerbates bleomycin-induced fibrosis (Fan et al., 2023; Hao et al., 2024; Chung et al., 2019). This in vivo experiment ties surfactant lipid output directly to mitochondrial fusion machinery that, in non-pulmonary tissues, also organises the LDMC interface, and supports the interpretation that surfactant assembly is coupled to mitochondrial fusion machinery—although the lamellar body itself is a lysosome-related organelle rather than a lipid droplet, so this coupling is a distinct organelle interaction rather than an LDMC in the strict sense. Within the lamellar body itself, surfactant protein SP-B drives membrane disc formation in the trans-Golgi network and shapes the multilamellar lattice via direct lipid–protein interaction, establishing a molecular template on which the LDMC machinery operatescontact-site biology. Within the lamellar body itself, surfactant protein SP-B drives membrane disc formation in the trans-Golgi network and shapes the multilamellar lattice via direct lipid–protein interaction, establishing a molecular template on which the LDMC machinery operates (Cañadas et al., 2020; Sever et al., 2021; Sun et al., 2024). Trafficking of the flippase ATP8A1 to lamellar bodies is in turn directed by the AP-3 sorting complex, and disruption of the AP-3/ATP8A1 interaction causes ATP8A1 retention in early or recycling endosomes, increases phosphatidylserine exposure on the cytosolic leaflet, and aberrantly activates the transcriptional coactivator Yes-associated protein (YAP), augmenting alveolar type 2 cell migration and number (Kook et al., 2021). This lamellar-body trafficking defect connects a lysosome-related-organelle delivery error to a YAP-driven repair programme that is genetically linked to Hermansky–Pudlak-syndrome pulmonary fibrosis, illustrating how an upstream LDMC-adjacent failure can rewire alveolar repair (Zeng and Yan, 2025).

Lipid metabolism within alveolar type 2 cells is also tightly coupled to mitochondrial ketogenesis. Downregulation of the mitochondrial ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in alveolar type 2 cells drives lipid accumulation, generates lysophosphatidylcholine species that activate adjacent fibroblasts, and accelerates pulmonary fibrosis; alveolar-type-2-specific HMGCS2 loss reproduces the fibrotic phenotype in mice (Yang et al., 2024; Chen X. et al., 2023). This places mitochondrial ketogenesis at the LDMC interface as a paracrine signalling output to fibroblasts. A complementary disease axis emerges in obesity-associated acute lung injury. High-fat-diet obesity combined with hyperoxia induces alveolar-type-2 intracellular lipid accumulation and increases CPT1A expression, yet transcriptionally downregulates mitochondrial fatty-acid oxidation and produces bioenergetic failure; alveolar-type-2-specific Cpt1a deletion exacerbates surfactant impairment and lung injury (Fan et al., 2023; Chen X. et al., 2023; Kallinos et al., 2025). The Kallinos finding is mechanistically central because it shows that elevated CPT1A protein does not equate to functional droplet-to-mitochondrion fatty-acid flow, and that the LDMC interface can be uncoupled at the regulatory level even when its core components are present. Alveolar type 2 cells therefore demand quantitative read-outs of contact-site engagement, not protein-level expression alone.

The cell-type-specific stoichiometry of PLIN5, PLIN2, MFN2, ESYT1/2, and MIGA2 in human alveolar type 2 cells, and how lamellar-body biogenesis remodels these stoichiometries during repair after viral or hyperoxic injury, has not been quantified at single-cell resolution. The PLIN5-S155 phospho-switch has not been mapped to lung-specific cues such as cyclic mechanical strain, oxygen tension, or surfactant turnover. Lipid-droplet–lamellar-body interconversion remains a structurally and mechanistically open question. The Sever lattice for lamellar-body assembly (Sever et al., 2021) and the Klein contact-site architecture (Klein et al., 2021) together provide complementary templates on which such work can be organised. The broader claim is that the alveolar type 2 cell is the most spatially complex LDMC compartment in the lung and that pharmacological engagement of the contact site here will require cell-type-precise delivery rather than systemic exposure (Pranty et al., 2026; Zeng and Yan, 2025).

2.2.2 Macrophages: surfactant recycling, cholesterol overload, and infection

Macrophages are the lung’s dominant lipid-recycling compartment. Alveolar macrophages reclaim surfactant from the alveolar lumen, while interstitial macrophages survey the parenchymal lipid pool. Both compartments rely on LDMC-coupled fatty-acid handling for resolution of inflammation, and both can be redirected into a lipid-laden, foam-cell-like phenotype that supports chronic disease.

Surfactant recycling is the alveolar macrophage’s signature task. CD44 loss in mice disrupts alveolar surfactant lipid homeostasis, sensitising the lung to oxidised-lipid–induced inflammation and identifying surfactant scavenging as a quantitatively important alveolar-macrophage function (Dong et al., 2020; Lee E. et al., 2024; Morán-Lalangui et al., 2025). Alveolar macrophages are anatomically and metabolically specialised for this loop; recent integrative reviews catalogue the cell type as a guardian of an alveolar lipid galaxy whose disturbance contributes to nearly every chronic lung disease (Xie et al., 2025; Little et al., 2025; Scur et al., 2022; Hernández-Hernández et al., 2024). The aetiological landscape of lipid-laden macrophages in the lung now spans aspiration, e-cigarette injury, immune deficiency, infection, and surfactant-handling defects, and each etiology rewires the LDMC interface in characteristic ways (Stevenson et al., 2023; Guerrini et al., 2020). When the recycling loop tips toward accumulation, the resulting lipid-laden macrophage phenotype amplifies inflammatory signalling, perpetuates injury, and resists therapeutic resolution; this phenotype unifies a broad swath of chronic lung disease across chronic obstructive pulmonary disease, IPF, tuberculosis, and acute lung injury (Zhu Y. et al., 2024; Stevenson et al., 2023; Guerrini et al., 2020), with additional cohort-derived foam-cell signatures supporting this convergence (Lee E. et al., 2024).

A cholesterol-driven axis has now been formally tied to chronic obstructive pulmonary disease. Plasma metabolomics in patients with stage III–IV disease, paired with a high-cholesterol-diet plus chronic cigarette-smoke mouse model and primary macrophage assays, identifies cholesterol overload as a driver of macrophage mitochondrial dysfunction, reactive-oxygen-species production, and downstream pro-inflammatory signalling (Ran et al., 2026). The result places cholesterol metabolism upstream of mitochondrial output in chronic obstructive pulmonary disease macrophages and motivates LXR-axis and statin re-investigation as LDMC-adjacent strategies in this population (Hernández-Hernández et al., 2024; Giambelluca et al., 2025; Ding et al., 2024).

In allergic asthma, the LDMC interface is reset toward fatty-acid oxidation in a tightly regulated way. Myeloid-specific deletion of fatty-acid-binding protein 5 (FABP5) increases free long-chain unsaturated fatty acids, most notably oleic acid, in macrophages and reprograms them toward alternative activation through enhanced β-oxidation, tricarboxylic-acid-cycle flux, oxidative phosphorylation, and PPARγ signalling; the result is more severe allergen-induced airway inflammation (Hou et al., 2022; Lu et al., 2025; Wu et al., 2026). FABP5 thus operates as a checkpoint that buffers free fatty-acid loading onto the LDMC interface in macrophages, and its loss tips the balance toward an M2 programme that potentiates asthma rather than resolving it. The Hou finding is important because it shows that LDMC engagement is not unidirectionally protective; the same droplet-to-mitochondrion flow that resolves macrophage inflammation in one setting can drive pathological alternative activation in another (Lu et al., 2025; Wu et al., 2026; Huang et al., 2022).

Tuberculosis provides the most extensively dissected example of LDMC remodelling under infection. Lipid-droplet formation in Mycobacterium tuberculosis-infected macrophages is now understood as a host-driven, IFN-γ/HIF-1α-dependent component of the immune response rather than a bacterially imposed nutrient depot; in vivo, HIF-1α and its target Hig2 are required for the majority of lipid-droplet formation in the lungs of infected mice, and these immune-driven droplets restrict Mtb lipid access while supporting host-protective eicosanoid production (Knight et al., 2018; Kalam et al., 2023; Mohareer et al., 2020; Mekonnen et al., 2021). A complementary axis defines the activation-state dependence of foam-cell formation. Interleukin-4-activated macrophages resist foam-cell conversion by routing droplet-derived fatty acids into mitochondrial fatty-acid oxidation, but direct Mtb infection forces a HIF-1α-driven aerobic-glycolytic shift that produces foam-cell macrophages; murine alveolar macrophages, which exhibit predominantly fatty-acid-oxidation metabolism, are correspondingly less prone to foam-cell conversion than bone-marrow-derived macrophages (Agarwal et al., 2021; Genoula et al., 2020; Chen et al., 2024). Macrophage fatty-acid metabolism therefore arbitrates antimicrobial outcome at the cellular level, and the contact-site interface offers a regulatable lever (Kalam et al., 2023; Mohareer et al., 2020; Chen et al., 2024; Laval et al., 2021). A second-generation question is whether droplet-derived fatty-acid channelling through PLIN5–FATP4 or MFN2 is the bottleneck through which alveolar macrophages maintain their fatty-acid-oxidation-protective phenotype.

In COVID-19, the same loop is hijacked by Severe acute respiratory syndrome coronavirus 2. ORF3a redirects lipid-droplet stores into replication-organelle biogenesis through induced microlipophagy, generating novel droplet-membrane contact sites that supply viral assembly with phospholipid precursors (Li Z. et al., 2025; Dias et al., 2020; Wang et al., 2023; López-Ayllón et al., 2024) in a process dependent on host lipid-droplet remodelling (Nardacci et al., 2021). This re-purposing of LDMC machinery for viral biogenesis suggests that LDMC-engagement modulators tested in chronic lung disease could be repositioned against acute viral pneumonia, although the cell-type selectivity needed for safety remains undefined.

Interstitial macrophages constitute a distinct LDMC-relevant compartment whose biology remains under-systematised in human respiratory disease. Unlike alveolar macrophages, interstitial macrophages are predominantly monocyte-derived under inflammatory conditions, occupy the lung parenchyma, and survey perivascular and peribronchial lipid pools. Their tether and flux machinery has not been profiled in IPF, chronic obstructive pulmonary disease, or asthma cohorts, even though single-cell transcriptomic surveys identify distinct lipid-metabolic profiles between the two macrophage compartments. Resolving interstitial-macrophage LDMC biology is a precondition for cell-type-selective inhaled delivery and constitutes a parallel research line to the foam-cell discussion above.

The macrophage compartment therefore presents LDMC biology in three operational modes, namely, surfactant recycling, cholesterol-driven inflammation, and infection-driven foam-cell formation. The PFKL–PLIN2–CPT1A axis, mechanistically established in hepatocellular carcinoma but not yet resolved in lung macrophages, is an attractive candidate target in this set by analogy, because it directly couples cytosolic glycolytic flux to contact-site-resolved oxidation and admits small-molecule intervention (Giambelluca et al., 2025; Huang et al., 2022).

2.2.3 Fibroblasts and myofibroblasts: A high-yield, under-resolved compartment

In the healthy lung, fibroblasts are mostly quiescent stromal cells with modest lipid reserves. After injury, however, a subset of resident interstitial fibroblasts and emergent pathological myofibroblasts undergoes a metabolic rewiring whose central feature is sustained matrix production at high energetic cost. We emphasise at the outset that no study has directly imaged or functionally quantified mitochondrion–lipid-droplet contact sites in primary lung fibroblasts; the LDMC relevance of this compartment is inferred from metabolic and transcriptomic data and from mechanisms established in other tissues. With that caveat, the bioenergetic and lipid requirements of the myofibroblast state make LDMC a plausible contributor to fibrotic biology, and the contact site has not been imaged at high resolution in primary lung fibroblasts as it has been in alveolar type 2 cells (Bezawork-Geleta et al., 2025; Klein et al., 2021).

Three converging lines of evidence motivate fibroblast LDMC as a research priority. First, single-cell transcriptomic reanalysis of idiopathic pulmonary fibrosis lungs identifies a coordinated upregulation of fatty acid oxidation, glycerolipid biosynthesis and cholesterol handling specifically in expanding myofibroblast clusters, with the strongest signal in clusters expressing collagen, smooth muscle actin and lipid-droplet scaffold genes (Bueno et al., 2020; Tian et al., 2023; Shi et al., 2024; Li W. et al., 2025). Second, mini-reviews of fatty-acid metabolism in idiopathic pulmonary fibrosis tie the same transcriptional programme to PPAR-γ/PGC-1α modulation, β-oxidation flux and aberrant prostaglandin/leukotriene signalling—pathways that depend on lipid-droplet-derived substrate delivery and mitochondrial respiratory capacity (Geng et al., 2021; Larson-Casey et al., 2020; MacIsaac et al., 2024). Third, broader synthesis of fibrotic lung disease metabolomics shows shared signatures across idiopathic pulmonary fibrosis, scleroderma-associated interstitial lung disease and post-COVID-19 fibrosis, including elevated lipid-droplet–associated transcripts and altered β-oxidation intermediates, suggesting that a common LDMC architecture supports myofibroblast persistence rather than being disease-specific (MacIsaac et al., 2024; Kumari et al., 2025; Siekacz et al., 2021; Nie et al., 2023).

A complementary signalling axis is the lysophosphatidic acid (LPA) pathway. LPA, generated from membrane lysophospholipids by the lung-enriched autotaxin (ENPP2), engages LPA receptor one on fibroblasts to drive proliferation, migration and contractile activation, and clinical-stage LPAR1 antagonism is now in late-phase idiopathic pulmonary fibrosis trials (MacIsaac et al., 2024; Nakamura and Shimizu, 2023). Although LPA signalling is conventionally framed as a G-protein-coupled cascade, the upstream LPA precursors are partitioned through lipid droplets, and the downstream Ca²⁺ and mTORC1 effectors converge on mitochondrial respiratory adaptation. The lipid-droplet–mitochondrion contact site is therefore the most parsimonious location at which LPA-driven biophysical signals are translated into the substrate availability that sustains procollagen biosynthesis and force generation. Alveolar-type-2 loss of HMGCS2, which precipitates lysophosphatidylcholine release and fibroblast activation (Yang et al., 2024), provides a paracrine link in the same direction: epithelial LDMC defects deliver lipid signals that fibroblasts must accommodate through their own contact-site biology.

The outstanding questions for fibroblast LDMC are pragmatic. Does the PLIN5-S155 phospho-switch (Benador et al., 2018; Kang et al., 2026) govern lipid mobilisation in myofibroblasts as it does in oxidative alveolar type 2 cells, and is its directionality reversed in pathological versus reparative fibroblast states? Are MIGA2-anchored endoplasmic-reticulum–lipid-droplet–mitochondria triple contacts (Freyre et al., 2019; Kim et al., 2022) enriched at sites of new collagen secretion, where the energetic cost of triple-helical assembly is greatest? Do PFKL puncta tether lipid droplets to mitochondria in lung myofibroblasts as they do in hepatocellular carcinoma cells (Meng et al., 2024), and would PFKL inhibition selectively de-energise pathological fibroblast clones without compromising regenerative repair? These questions are tractable with current imaging and conditional-genetic tools but remain unanswered, marking fibroblast LDMC as a high-yield gap and the most likely venue for repurposing nintedanib and LPAR1 antagonists with LDMC-axis modulators in idiopathic pulmonary fibrosis combination regimens, drawing on mitochondrial-quality-control and lipid-handling pathways (Larson-Casey et al., 2020; Siekacz et al., 2021; Nie et al., 2023) and IPF-specific ECM and respiratory-physiology read-outs (Li W. et al., 2025).

2.2.4 The pulmonary endothelium: the field’s largest gap

The pulmonary endothelium presents the most poorly resolved compartment in the LDMC literature, and this gap is one of the central scientific observations of the present review. To state it directly: no study has demonstrated LDMC contact sites in pulmonary endothelium, and every mechanism discussed in this subsection is inferred from endothelial metabolic dependence, cross-tissue analogy, or mitochondrial-transfer therapeutics. Pulmonary microvascular endothelial cells are highly dependent on fatty-acid β-oxidation for membrane phospholipid biosynthesis during proliferation and barrier maintenance, yet whether LDMC contact sites specifically structure that dependence in the lung capillary bed remains experimentally untested with the methods available for alveolar type 2 cells, macrophages or fibroblasts (Shi et al., 2024), even though endothelial lipid-handling datasets provide a useful starting point (Lee et al., 2022; Pokharel et al., 2023).

The strongest current evidence enters indirectly, through mitochondrial-transfer therapeutics. Caldeira and colleagues demonstrated in 2025 that mesenchymal stromal cell-derived mitochondria are taken up by human pulmonary microvascular endothelial cells exposed to lipopolysaccharide or to plasma from hyper-inflammatory acute respiratory distress syndrome (ARDS) patients, restoring mitochondrial respiration and barrier integrity in vitro and attenuating lung injury in lipopolysaccharide-challenged mice (de Assis Fernandes Caldeira et al., 2025; Wang J. et al., 2025). The therapeutic mechanism implies that pulmonary endothelial mitochondria are limiting under inflammatory stress, and the lipid-handling capacity of recipient cells must adapt to the supplied mitochondria, but the contact-site biology has not been examined directly. Whether donor mitochondria establish productive LDMC contacts in recipient endothelium, whether endogenous PLIN-decorated lipid droplets in pulmonary endothelium ferry fatty acids to those mitochondria, and whether PFKL–PLIN2 tethering, a mechanism demonstrated only in hepatocellular carcinoma, operates in endothelium at all, and how the inflammatory milieu rewires endothelial PFKL–PLIN2 tethering are all open (Meng et al., 2024).

The case for a focused experimental campaign is strong. The pulmonary capillary bed is the obligate first-pass site for postprandial chylomicron remnants, and endothelial LDMC is a plausible regulator of pulmonary hypertension, ARDS, fibrotic vascular remodelling and tumour vasculogenesis. The minimum first set of experiments would be live-cell imaging of lipid-droplet–mitochondrion contact dynamics in primary human pulmonary microvascular endothelial cells under inflammatory and hypoxic conditions, paired with PLIN5-S155 and MIGA2 perturbations and respiratory phenotyping drawing on existing endothelial datasets (Zhang and Michelakis, 2021; Nukala et al., 2021; Flerlage et al., 2023) and pulmonary microvascular and ARDS models (Zhu L. et al., 2024; Yao et al., 2026; Wang F. et al., 2025). Without that dataset, the endothelial compartment will continue to be reasoned about by analogy rather than evidence—a state the field can no longer accept given the centrality of pulmonary vasculature to most of the diseases enumerated below (Nukala et al., 2021; Wang F. et al., 2025).

2.2.5 Lung adenocarcinoma: the only lung compartment with direct LDMC evidence

Lung adenocarcinoma (LUAD) is the most common lung cancer histology and the only lung disease in which LDMC has been directly demonstrated by contact-resolving methods. Han and colleagues used spatial proteomics and electron tomography across human LUAD samples to map mitochondrial network topology and bioenergetics in situ, and their landmark dataset established that high-grade LUAD regions exhibit dense lipid-droplet–mitochondrion contact sites, oxidative-phosphorylation-leaning tumour cells, and a metabolic geography in which peridroplet mitochondria support cellular respiration in lipid-rich microenvironments (Han et al., 2023; Jin and Yuan, 2020; Liu et al., 2023). Separately, Meng and colleagues reported in 2024 that PFKL, long regarded as a purely glycolytic enzyme, is a bifunctional protein whose puncta tether lipid droplets to mitochondria through PLIN2 and recruit CPT1A to the contact, thereby coupling cytosolic glycolytic flux to β-oxidation and tumour growth. Critically, that mechanism was established in hepatocellular carcinoma, not in lung cancer; its relevance to LUAD is inferred from the shared peridroplet mitochondrial geography mapped by Han and colleagues, and it has not been experimentally demonstrated in lung tissue. The PFKL–PLIN2–CPT1A axis is arguably the most experimentally complete LDMC tether-and-flux mechanism in any disease context, but it was established in liver, not lung: PFKL puncta physically dock PLIN2-decorated lipid droplets to mitochondria, recruit CPT1A and ATGL, and channel free fatty acids into β-oxidation (Meng et al., 2024). If this dual role operates in LUAD, it could help explain why glycolysis-targeted therapy has had limited efficacy in oxidative-phosphorylation-leaning tumours: the same enzyme also organises the contact-site machinery that supports oxidative metabolism. Testing that inference in lung models is a priority experiment.

Several streams of evidence implicate the perilipin family directly in LUAD progression. Miyata-Morita and colleagues demonstrated in human LUAD cohorts that high PLIN2 expression associates with poor differentiation, blood-vessel and pleural invasion, advanced stage and shorter recurrence-free survival, and that CRISPR/Cas9 PLIN2 knockout in A549 and PC-9 cells reduces lipid-droplet accumulation, suppresses oleic-acid–induced lipid-droplet formation, and impairs proliferation and migration (Gründing et al., 2022; Miyata-Morita et al., 2025). PLIN3, in a pan-cancer analysis with focused LUAD validation, is upregulated in tumours, correlates with adverse prognosis, and recruits M2 tumour-associated macrophages, establishing a paracrine axis through which tumour LDMC restructures the immune microenvironment (Torresano et al., 2022; Yang et al., 2025). Earlier in vitro work showed that lipid droplets themselves are critical for LUAD cell growth and starvation survival, indicating that perilipin-decorated lipid-droplet stores function as substrate reservoirs rather than as inert lipid sinks (Lung et al., 2022).

CPT1A is the prevailing β-oxidation entry point in LUAD LDMC. Ma and colleagues, using a lung-epithelium-specific Cpt1a knockout mouse, demonstrated that CPT1A suppresses ferroptosis in cancer stem cells through a c-Myc-positive feedback loop that activates the NRF2/GPX4 axis and downregulates ACSL4, and that pharmacological CPT1A inhibition synergises with immune checkpoint blockade to enhance both anti-tumour immunity and tumoural ferroptosis (Ma et al., 2024). Xu and colleagues complemented this finding by showing that miR-365-3p, downregulated in lung cancer, normally suppresses CPT1A translation; loss of miR-365-3p drives the lipid-droplet–CPT1A–fatty-acid-oxidation axis to support proliferation and migration, and rescue experiments confirm that the proliferative phenotype is fatty-acid-oxidation-dependent (Xu et al., 2025; De Oliveira and Liesa, 2020). Together, these genetic and pharmacological data place CPT1A at the centre of a candidate LDMC vulnerability in LUAD, demonstrated at the level of CPT1A-dependent fatty-acid oxidation and ferroptosis resistance, with the contact-site tether itself inferred from hepatocellular carcinoma, that interlocks with two of the most active areas in lung cancer therapeutics: immune checkpoint inhibition and ferroptosis induction.

A translational precedent exists. Cai and colleagues constructed and validated a lipid-droplet–mitochondria-associated risk score from eight genes that stratifies LUAD survival and immunotherapy response in TCGA cohorts, providing a precedent for LDMC-derived clinical decision tools (Cai et al., 2024). Reviews of broader lipid-metabolism reprogramming in epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer also implicate fatty acid synthase, stearoyl-CoA desaturase and sterol regulatory element-binding protein in tyrosine kinase inhibitor resistance, and these pathways converge on lipid-droplet biogenesis and remodelling (Eltayeb et al., 2022). The unresolved question is whether the PFKL–PLIN2–CPT1A axis acts as the master regulator of these downstream effectors or operates as one of several parallel routes, a distinction whose resolution determines whether single-target or combination LDMC therapy is the appropriate translational strategy in LUAD. Together, the LUAD evidence base shows that LDMC is directly demonstrated in lung cancer by spatial proteomics and electron tomography, while the central tether-and-flux mechanism (PFKL–PLIN2–CPT1A) remains extrapolated from hepatocellular carcinoma; LUAD therefore provides the most mature, but still partly inferential, template against which other lung diseases are benchmarked.

2.3 The disease matrix: cell-type-resolved failure modes across respiratory illness

The same LDMC machinery acquires disease-specific configurations across the spectrum of respiratory illness. This synthesis identifies, for each disease, the dominant LDMC failure mode, the most experimentally tractable cell-type entry point, and the therapeutic question that emerges. The full disease-to-failure-mode-to-therapy matrix is presented as a Sankey diagram in Figure 3 and expanded row-by-row in Table 3, with representative references retained per disease.

FIGURE 3

Idiopathic pulmonary fibrosis (IPF). IPF combines alveolar-type-2 mitochondrial dysfunction, alveolar-type-2-derived lipid signalling to fibroblasts, and a macrophage compartment that resists apoptosis. Mitofusin-mediated alveolar-type-2 lipid metabolism failure drives spontaneous fibrosis in mice (Chung et al., 2019), HMGCS2 downregulation in alveolar type 2 cells releases lysophosphatidylcholine and activates fibroblasts (Yang et al., 2024), and alveolar-type-2 mitochondrial permeability transition pore opening propagates the injury (Larson-Casey et al., 2020; MacIsaac et al., 2024; Lu et al., 2024). In the macrophage compartment, Cpt1a interacts with mitochondrial Bcl-2 in IPF lung macrophages to drive apoptosis resistance and fibrotic remodelling, providing the most explicit macrophage-LDMC mechanism in chronic lung disease (Gu et al., 2022). The dominant failure mode is therefore distributed across alveolar, mesenchymal and macrophage compartments rather than localised to a single cell type, which explains why monotherapy with nintedanib or pirfenidone slows but does not arrest disease (Bonella et al., 2023). The most tractable LDMC intervention is the Cpt1a–Bcl-2 axis in macrophages paired with alveolar-type-2 mitochondrial protection (Wang et al., 2024a). Mechanistically, Cpt1a binds the BH3 domain of mitochondrial Bcl-2 to suppress macrophage apoptosis, sustaining the lipid-laden macrophage population that drives fibrogenic crosstalk with alveolar type 2 cells and fibroblasts (Gu et al., 2022) (Siekacz et al., 2021). The implication is that anti-apoptotic CPT1A–Bcl-2 disruption could deplete pro-fibrotic macrophages without targeting epithelial CPT1A (MacIsaac et al., 2024).

Chronic obstructive pulmonary disease (COPD). COPD pathogenesis converges on cigarette-smoke-driven oxidative stress, alveolar macrophage dysfunction, and cholesterol-driven metabolic reprogramming. Multi-omics analysis of human COPD samples integrated with cigarette-smoke and high-cholesterol-diet mouse models established cholesterol-driven macrophage mitochondrial dysfunction, reactive oxygen species generation, and downstream inflammation as a quantitatively dominant axis (Ran et al., 2026). Recent synthesis positions ferroptosis, driven by iron-catalysed peroxidation of polyunsaturated fatty acids in membrane phospholipids and amplified by DRP1-mediated mitochondrial fission and lipid-droplet–mitochondria contact remodelling, as a unifying mediator of COPD pathology (Ni et al., 2026; Manevski et al., 2020). The COPD foam-cell phenotype is part of a unifying lipid-laden-macrophage state that also encompasses tuberculosis, silicosis and acute lung injury (Manevski et al., 2020). The cell-type entry point is the alveolar macrophage; the therapeutic question is whether LDMC stabilisation upstream of ferroptosis can be achieved without compromising clearance of inhaled lipid loads (Fairley et al., 2023).

Asthma. Asthma extends the macrophage LDMC narrative into adaptive-immune-driven disease. FABP5 deletion in myeloid cells enhances IL-4-driven M2 polarisation and aggravates allergic airway inflammation in murine models, with the mechanism traced to oleic-acid accumulation, fatty-acid-oxidation upregulation, tricarboxylic-acid-cycle activation and PPAR-γ signalling (Wang et al., 2026). Asthmatic macrophages therefore present an LDMC state that is permissive for, rather than resistant to, allergic inflammation, and the dominant failure mode is dysregulated lipid trafficking rather than impaired bioenergetics. The therapeutic question is whether selective restraint of macrophage fatty-acid oxidation can attenuate exacerbations without disrupting host defence, which itself depends on macrophage lipid handling (Esteves et al., 2021; Ravi et al., 2021), and viral and asthma-cohort macrophage profiles (Hartsoe et al., 2024; Ni et al., 2025).

Silicosis and pneumoconiosis. Inhalation of mineral dusts produces persistent alveolar macrophage activation and lipid-laden macrophage accumulation that resemble the COPD and tuberculosis foam-cell phenotypes but are sustained by chronic exogenous lipid input. The dominant failure mode is recurrent lipid uptake without effective resolution: the alveolar macrophage compartment cannot complete the surfactant-recycling loop. The therapeutic question is whether LDMC stabilisation could shift mineral-laden macrophages toward a pro-resolution state and prevent progression to fibrotic remodelling (Adamcakova and Mokra, 2021).

Acute respiratory distress syndrome (ARDS). ARDS is dominated by acute endothelial barrier failure superimposed on alveolar epithelial injury, with mitochondrial dysfunction and pulmonary oedema as principal mediators (Robinson and Krasnodembskaya, 2020). The strongest LDMC-adjacent therapeutic evidence is in this disease. Pulmonary endothelial mitochondrial dysfunction induced by lipopolysaccharide or by hyper-inflammatory ARDS patient plasma is reversed by transplantation of mesenchymal-stromal-cell-derived mitochondria, restoring barrier integrity in primary human pulmonary microvascular endothelial cells and attenuating injury in lipopolysaccharide-challenged mice (de Assis Fernandes Caldeira et al., 2025). A complementary line of work demonstrated that mitochondrial transplantation alleviates lipopolysaccharide-induced ARDS through reduction of alveolar inflammation and apoptosis (Lee S-E. et al., 2024). CPT1A overexpression in alveolar epithelium also alleviates lipopolysaccharide-induced acute lung injury, identifying CPT1A as a candidate pharmacological target (Wang G-Y. et al., 2024; McClintock et al., 2022; Shen et al., 2024). The cell-type entry point is the pulmonary microvascular endothelium and the alveolar type 2 cell in parallel (Flerlage et al., 2023; Wang F. et al., 2025).

Tuberculosis. Mycobacterium tuberculosis exploits and rewires macrophage LDMC. Lipid-droplet formation in infected macrophages is not pathogen-driven but is an interferon-γ-induced, HIF-1α–dependent host-defence programme required for granuloma function (Kalam et al., 2023), while direct mycobacterial infection counteracts the alternative-activation fatty-acid-oxidation programme that would otherwise prevent foam-cell formation, driving glycolytic metabolic reprogramming and tissue-damaging lipid accumulation (Shim et al., 2020). Macrophage fatty-acid metabolism therefore arbitrates infection outcome. The therapeutic question is whether host-directed therapy that nudges LDMC toward the IFN-γ/HIF-1α-protective configuration could shorten antibiotic-treatment duration without rebound inflammation. Alveolar macrophages appear less prone to glycolytic foam-cell conversion than bone-marrow-derived macrophages, raising the possibility of compartment-specific effects: an LDMC modulator may benefit interstitial macrophage states without disturbing alveolar macrophage host defence (Genoula et al., 2020; Laval et al., 2021). This cell-type stratification has not been incorporated into any tuberculosis host-directed therapy trial (Chen et al., 2024; Shim et al., 2020).

COVID-19. SARS-CoV-2 hijacks lipid-droplet–mitochondria flux through ORF3a-induced microlipophagy to deliver lipid substrates for replication-organelle biogenesis, demonstrating a viral subversion of LDMC architecture. Broader profiling of metabolic alterations after SARS-CoV-2 infection has mapped extensive remodelling of lipid metabolism, fatty-acid biosynthesis, and mitochondrial function, identifying multiple potential therapeutic targets (Chen P. et al., 2023; Cevallos et al., 2025; Park, 2025). The dominant failure mode is acute viral co-option, and the therapeutic question is whether host LDMC stabilisation could reduce viral fitness without compromising the antiviral interferon response (D’Avila et al., 2024).

Lung adenocarcinoma (LUAD). LUAD is the only disease in the matrix with direct LDMC evidence (spatial proteomics and electron tomography of peridroplet mitochondria), and it serves as the benchmark for what cell-type-resolved LDMC therapy looks like when the molecular pieces are in place while noting that its central tether mechanism (PFKL–PLIN2–CPT1A) is extrapolated from hepatocellular carcinoma: PLIN2 as a prognostic biomarker (Miyata-Morita et al., 2025), PLIN3 as a tumour-associated-macrophage-interfacing target, CPT1A as a ferroptosis-resistance node (Ma et al., 2024), the PFKL–PLIN2–CPT1A flux axis (established in hepatocellular carcinoma, inferred in LUAD) as a candidate central regulator, and an eight-gene lipid-droplet–mitochondria risk score that already stratifies patients in TCGA cohorts (Cai et al., 2024). Outside LUAD, the matrix is dominated by gaps that the next section translates into a programmatic translational pipeline.

3 Translational pipeline

The cell-type-resolved LDMC mechanisms summarised above, graded by evidence tier, support an integrated translational research programme rather than a list of disconnected hypotheses. Four therapeutic routes have preclinical proof of concept in respiratory disease: small-molecule modulation of contact-site tethers and flux nodes, inhaled lipid-nanoparticle delivery of LDMC-targeted payloads, mitochondrial transplantation, and combination repurposing of approved antifibrotics or immune checkpoint inhibitors with LDMC-axis modulators. Each route carries a specific safety constraint that should shape further development (Wan et al., 2023; Al-Jipouri et al., 2023; Zong et al., 2024).

3.1 Four operational routes

Small-molecule LDMC modulation. The PFKL–PLIN2–CPT1A axis is the most experimentally complete LDMC pharmacological target in principle, but its evidence base is split: the molecular tether is mapped in hepatocellular carcinoma (not lung), whereas the catalytic CPT1A node is demonstrated in LUAD models and addressable with preclinical tool inhibitors such as etomoxir (Wang G-Y. et al., 2024), and the downstream lipid-droplet–mitochondria risk score validated in LUAD cohorts (Ma et al., 2024; Cai et al., 2024). CPT1A inhibition in tumour models synergises with immune checkpoint blockade through ferroptosis induction (Ma et al., 2024), and CPT1A overexpression alleviates lipopolysaccharide-induced acute lung injury (Wang G-Y. et al., 2024), framing CPT1A modulation as a context-dependent therapy whose direction of perturbation must match disease context (Zong et al., 2024). The Cpt1a–Bcl-2 interaction in lung macrophages provides an additional macrophage-selective target with anti-fibrotic potential (Gu et al., 2022). The corresponding safety constraint is bidirectional. Off-target CPT1A inhibition could compromise epithelial barrier defence, where higher CPT1A is protective in acute lung injury (Wang G-Y. et al., 2024), while necessary for anti-tumour or anti-fibrotic effects, so cell-type-selective delivery and on-tissue pharmacodynamic biomarkers are required. A further constraint is pharmacological: etomoxir itself is not clinically accessible. At the concentrations commonly used to inhibit CPT1A it induces severe oxidative stress and CPT1A-independent off-target effects, including direct inhibition of mitochondrial respiration, and it has never advanced beyond experimental use (Al-Jipouri et al., 2023; Zong et al., 2024; K and Narayansamy, 2025; O’Connor et al., 2018).

Inhaled lipid-nanoparticle delivery. The inhaled route is uniquely suited to LDMC pharmacology in the lung because it concentrates drug at the relevant cell types while limiting systemic exposure. Two preclinical proof-of-concept studies anchor the route. Mucus-penetrating inhalable lipid nanoparticles co-delivering messenger RNAs encoding cytochrome b5 reductase three and bone morphogenetic protein four to alveolar type 2 cells restore stemness and trigger realveolarisation in bleomycin-induced mouse fibrosis, the most direct demonstration that LDMC-adjacent epithelial biology can be reprogrammed in vivo (Wan et al., 2023; Bai et al., 2024). A separate nanomedicine targeting the mitochondrial permeability transition pore through coordinated cyclophilin D inhibition (by a cyclosporin-A-derived ionisable lipid) and mitochondrial calcium uniporter silencing achieves “double braking” on alveolar-type-2 mitochondrial dysfunction in IPF mouse models (Liu et al., 2022; Li D. et al., 2023; Wang et al., 2024c). Inhaled specialised pro-resolving mediator-based nanotherapeutics target the macrophage lipid-droplet–NLRP3 axis and the epithelial reactive-oxygen-species–TGF-β/Smad pathway in parallel, attenuating bleomycin- and engineered-nanomaterial-induced fibrosis (Liu et al., 2022; Li D. et al., 2023; Li J. et al., 2023; Bai et al., 2022), with additional inhaled-fibrosis nanotherapeutic platforms in active development (K and Narayansamy, 2025; Deng et al., 2025). The safety constraint is alveolar deposition kinetics in fibrotic lungs, where mucus and matrix barriers may divert payload from intended cells; head-to-head pharmacokinetic studies in human ex vivo lung tissue are the immediate gap (Wan et al., 2023; Al-Jipouri et al., 2023; K and Narayansamy, 2025; Zimmermann et al., 2022).

Mitochondrial transplantation. Two independent preclinical lines support the transplantation route in ARDS. Mesenchymal-stromal-cell-derived mitochondria are taken up by human pulmonary microvascular endothelial cells and restore both mitochondrial respiration and barrier integrity in vitro and in lipopolysaccharide-challenged mice (de Assis Fernandes Caldeira et al., 2025); exogenous mitochondrial transfer alleviates lipopolysaccharide-induced ARDS through suppression of alveolar inflammation and epithelial/endothelial apoptosis (Lee S-E. et al., 2024). The mechanism is mitochondrial replacement, but the lipid-handling capacity of recipient cells must accommodate the supplied mitochondria, raising LDMC questions that have not yet been addressed in transplantation studies. The safety constraint is donor mitochondrial mismatch (mitochondrial DNA heteroplasmy effects), pulmonary embolism risk from particulate delivery, and the unknown durability of effect. Phase one studies in adult ARDS have been proposed on the basis of manufacturing and regulatory groundwork laid for paediatric cardiac surgery transplantation (Wang et al., 2024c).

Combination repurposing. The deepest translational lever is the combination of approved or late-stage agents with LDMC-axis modulators. Nintedanib and pirfenidone slow but do not arrest IPF progression (Bonella et al., 2023), and the LDMC literature now identifies alveolar-type-2 mitochondrial protection and Cpt1a–Bcl-2 disruption in macrophages as biologically complementary mechanisms, supported by mRNA- and antifibrotic-LNP combination strategies (Bai et al., 2022; Deng et al., 2025) and ROS-responsive or pro-resolution platforms (Li D. et al., 2023; Wang et al., 2024c). LPA-receptor antagonism, an active area of late-stage IPF drug development, is positioned within the LPA–fibroblast axis that is itself coupled to lipid-droplet–mitochondria–endoplasmic-reticulum tripartite contacts and to alveolar-type-2 epithelial dysfunction. Immune checkpoint blockade in LUAD remains response-limited, and CPT1A inhibition synergises through ferroptosis induction, providing the prototype for LDMC-targeted combination immuno-oncology. Tension-induced organelle stress is emerging as a tractable mechanism in fibrosis with overlap to LDMC at the contact-site mechanical interface (Kai et al., 2025), and ARDS metabolic targeting is moving from concept toward early clinical translation (Robinson and Krasnodembskaya, 2020; Wang G-Y. et al., 2024). The safety constraint across all combinations is overlapping toxicity at the mitochondrion, where simultaneous perturbation of multiple respiratory or LDMC nodes can precipitate respiratory failure rather than fibrosis arrest. Sequential rather than concurrent dosing, with mitochondrial respiratory-reserve monitoring as a pharmacodynamic biomarker, is the conservative path forward.

4 Discussion

The synthesis assembled across the preceding sections converges on a single view. The lipid droplet and mitochondrion, once studied as two separate compartments of energy economy, are now best understood as a single addressable interface whose molecular composition, phosphorylation logic and spatial geometry can be enumerated, perturbed and quantified in living cells (From the American Association of Neurological Surgeons AANS et al., 2018). That interface belongs to a broader class of inter-organelle contact sites whose recognition as pharmacologically tractable interfaces has moved beyond exploratory imaging into a systematic research programme, and consensus criteria now exist for what counts as a defined contact, how it should be measured and how it should be reported (Calì et al., 2025). Within this framework the alveolus offers a rare configuration where every relevant cell type engages the same interface with a distinct stoichiometry and outcome, so that a single molecular axis can appear cytoprotective, homeostatic, immunopermissive or oncogenic depending on the compartment in which it operates. The pharmacological consequences are already being tested through a modest but growing catalogue of small molecules that either restore, tighten or dissolve specific contacts, and the design principles that underlie their selectivity are becoming articulable rather than empirical (Ko et al., 2026). What remains missing is not a further list of molecular players, since the field is now data-rich, but an integrating framework that couples flux measurement to spatial context so that the interface can be evaluated in whole tissues under disease-relevant perturbation (Mathiowetz and Olzmann, 2024). The chapters below take up that missing framework by asking what the interface still hides at the mechanistic level, where the current experimental paradigm is falling short, and how those two constraints will shape the next decade of translation.

The mechanistic ground under this interface, though far better characterised than 5 years ago, still hides several questions whose resolution will constrain any therapeutic development that follows. Foremost among them is the compartmental duality of CPT1A, the enzyme that authorises fatty acid entry into the mitochondrial matrix. In alveolar macrophages under acute injury the IL-10-linked CPT1A programme restrains inflammatory activation and limits epithelial damage (Wang M. et al., 2024), whereas in tumour and chronically-stressed macrophage settings the same enzyme sustains membrane integrity, blocks ferroptosis and supports survival despite ongoing lipid overload (Shi et al., 2025). Whether the two phenotypes reflect a shared catalytic activity read out through divergent downstream signalling, or a genuinely different flux regime driven by cell-type-specific co-factors and isoform partitioning, cannot be resolved without single-cell lipid-flux measurement that treats compartment and time as first-class variables. Related uncertainty attaches to phosphorylation-based tether regulation, where site-level information such as PLIN5 S155 occupancy governs whether a droplet feeds or sequesters lipid, yet genotype and steady-state transcript readouts collapse this dimension entirely; only through recent gains in phosphoproteomic sensitivity can stoichiometry now be tracked across subcellular fractions with the confidence needed for causal interpretation (Muneer et al., 2025; Lancaster et al., 2024). Answering these questions in native human tissue further depends on whether the transcriptional signatures already reported in lung adenocarcinoma correspond to genuine, perturbation-sensitive drug targets rather than incidental high-expression correlates. Patient-derived organoids from resected material and pleural fluid now generate perturbation readouts in clinically actionable timescales and preserve enough of the native metabolic wiring to test tether-level hypotheses in matched genetic backgrounds (Lee S-H. et al., 2024). Mechanistic ambition therefore no longer outstrips experimental capacity, but the remaining bottleneck sits at the paradigmatic level rather than at the level of individual assays.

Three features of the current experimental paradigm limit how quickly mechanistic insight will convert into clinical use, and each admits a specific methodological remedy that the field is now beginning to adopt. Species mismatch is perhaps the most consequential of these, because mouse and human lungs diverge in alveolar architecture, surfactant lipid composition and epithelial repair trajectories, and spatially-resolved comparisons of transcriptomic and cell-state maps have made those divergences quantifiable rather than anecdotal (Franzén et al., 2024). What follows is that a pharmacologically tractable node identified in a mouse model of fibrosis or macrophage lipotoxicity should be re-tested in a human air-liquid interface or organoid preparation before any target-validation claim is made, and the case for parallel-species pipelines rather than sequential-species pipelines is now backed by explicit road-map proposals (Cantor, 2025). Dimensional undersampling introduces a distinct but equally serious distortion, since membrane contact sites are three-dimensional geometries with a defined intermembrane gap and an area that cannot be recovered from single confocal slices; expansion microscopy and volumetric electron approaches now provide the resolution needed to score contact area and stoichiometry directly, and consensus workflows increasingly recommend that any imaging-based tether claim be corroborated across two orthogonal modalities before biological weight is assigned (Diokmetzidou and Scorrano, 2025; Zhuang et al., 2026; Marshall et al., 2023). Compounding both problems, cell-type-specific tether configurations are averaged out in bulk transcriptomics, so signatures derived from whole-lung homogenates conflate donor cells that behave in opposite metabolic directions, a limitation surfaced most clearly for alveolar macrophage lipid programmes where subset-level heterogeneity carries most of the disease signal (Apte et al., 2026). Aligning assay resolution with biological resolution therefore becomes as decisive as any additional mechanistic discovery for what follows, which is the translation of these interfaces into patient benefit.

Patient benefit will depend on several interlocking developments, and their order is set by scientific readiness rather than by ambition. Delivery is the most immediately tractable of these. Inhaled lipid nanoparticles offer a route to alveolar cells that bypasses first-pass metabolism, yet the endogenous surfactant film redistributes cargo and imposes screening demands that most efficacy studies still under-report; formulations that co-engineer particle surface and surfactant interaction, and that measure delivery quantitatively before invoking efficacy, are now moving from proof of concept into pulmonary-relevant preclinical work (Kassab et al., 2023; Falahati et al., 2023; Gonsalves and Menon, 2024). Trial architecture must move in step with delivery, because responder heterogeneity in interstitial and airway diseases has been the principal reason that mechanistically-plausible agents have failed at Phase II or III when tested against unstratified cohorts. Adaptive platforms that permit multiple arms, biomarker-enrichment stages and Bayesian response-adaptive randomisation are now operational for fibrotic lung disease and provide the trial-design substrate into which lipid-mitochondria interface signatures can be embedded (Kawano-Dourado et al., 2024). Beneath both delivery and trial design, precision-medicine work in idiopathic pulmonary fibrosis has moved from taxonomic descriptions of endotype toward composite molecular scores intended for enrichment, so that any interface-derived signature must fit into this framework if it is to become a companion diagnostic rather than a research instrument (Karampitsakos et al., 2023). Underpinning all of the above, biomarker maturity itself will depend on pre-analytic discipline in bronchoalveolar lavage, because the dilution problem, storage stability and cell-type composition have historically defeated attempts to compare lavage-derived measurements across sites; consensus normalisation and standardisation frameworks are now proposed and warrant broad adoption before any Phase Ib trial invokes lavage-based stratification (Haeger et al., 2024; Mawer et al., 2026). Aligning delivery, design, framework and pre-analytic rigour is what will convert the interface catalogued here into a clinical instrument, and each of these components is now defensible on published evidence rather than aspirational.

Biomarker stratification for LDMC-directed trials divides into validated and exploratory candidates, distinguished by sample type and assay. Two biomarkers are validated in the strict sense of reproducible association with clinical outcome in patient cohorts. PLIN2, measurable by immunohistochemistry or transcriptomics in resected tumour or biopsy tissue, stratifies differentiation, invasion and recurrence-free survival in lung adenocarcinoma. The eight-gene lipid-droplet-mitochondria risk score, computed from bulk tumour transcriptomes, stratifies survival and immunotherapy response in TCGA lung adenocarcinoma cohorts. All remaining candidates are exploratory. PLIN5-S155 phosphorylation occupancy would require a phospho-specific antibody assay applied to bronchoalveolar lavage cells or transbronchial biopsy, and has not been validated in any lung cohort. Contact-site occupancy itself is measurable only by imaging, whether super-resolution or electron microscopy of biopsy material, and is not yet standardised across sites. Mitochondrial respiratory reserve, measurable by extracellular-flux assay in live cells from lavage or biopsy, is a functional pharmacodynamic readout rather than a contact-site-specific one. We recommend that early-phase LDMC trials embed the two validated biomarkers for patient selection and carry the exploratory set as secondary pharmacodynamic endpoints, so that biomarker maturity can advance in parallel with the therapeutics.

Several limitations qualify the synthesis presented here. Direct evidence in human respiratory tissue remains scarce, since only one dataset, spatial proteomics with electron tomography in non-small cell lung cancer (Han et al., 2023; Jin and Yuan, 2020; Liu et al., 2023), resolves lipid-droplet–mitochondria contacts in lung; cryogenic correlative microscopy in alveolar type 2 cells (Klein et al., 2021) resolves lamellar-body–mitochondria juxtaposition, a distinct organelle interaction that we do not classify as LDMC, and most mechanisms discussed are extrapolated from metabolic or transcriptomic data or from other tissues. Quantifying functional contacts is also technically difficult, because membrane contact sites are three-dimensional and dynamic geometries, and no standardised assay yet reports contact-site number, area or flux in primary human lung cells. Even where imaging is available, colocalization by light microscopy is not evidence of a functional contact, and several lung studies cited here rely on proximity signals that have not been corroborated by orthogonal ultrastructural or flux-based methods. The pharmacological tools introduce a further caveat, in that etomoxir, the most widely used CPT1A inhibitor, exhibits dose-dependent off-target effects including oxidative stress and direct respiratory inhibition at commonly used concentrations, so conclusions drawn from it require independent genetic confirmation (Yao et al., 2018). Finally, cell-state and disease-stage variability across macrophage subset, fibroblast activation state and tumour grade means that the LDMC configurations catalogued here are likely to shift within a given disease, and most cited studies capture only a single state. These limitations define the agenda of Section 4 as much as the discoveries do.

5 Conclusion

LDMC has moved from a descriptive cell-biological curiosity into a mechanistically tractable, cell-type-resolved interface with emerging pharmacological relevance. Its application to respiratory medicine, however, remains uneven, and three specific gaps determine what comes next. The pulmonary endothelium is the field’s largest evidence gap, since no primary study has resolved contact-site dynamics in human pulmonary microvascular endothelial cells under inflammatory, hypoxic or fibrotic stress, and closing that gap is now within experimental reach. Beyond it, the lipid-mechanics interface remains unformalised: contact-site geometry stands at the point at which cytoskeletal tension could be transduced into lipid-flux change, but this transduction has not yet been formally tested in lung fibroblasts. Beyond both, operational biomarkers are still missing, because the field lacks validated readouts of phospho-switch occupancy or interface engagement that survive translation into bronchoalveolar lavage, sputum or biopsy material. A coordinated programme that closes these gaps would convert LDMC from a productive area of basic discovery into the cell-type-resolved therapeutic discipline that lung-disease patients have not yet benefited from in the way that liver-disease patients are beginning to. The molecular toolkit is in place, the disease anchors are mapped, the translational routes are identified, and the remaining work is execution.

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