Glycolytic flux can result in changes in the pentose phosphate pathway (PPP), the hexosamine biosynthesis pathway (HBP), serine biosynthesis, and the tricarboxylic acid (TCA) cycle, promoting CC development (64). Rate-limiting glycolytic enzymes, such as hexokinase 1/2 (HK1/2), phosphofructokinase 1, and lactate dehydrogenase A (LDHA), are upregulated to facilitate the Warburg effect, resulting in glycolytic flux and the production of lactate from glucose in PDAC-CC (63, 64). The upregulation and translocation of glucose transporters (GLUT1, encoded by SLC21A) in tumor tissues facilitate glucose uptake for aerobic glycolysis. Increased glycolytic flux in response to host–tumor interactions in cachexia results in the production of high lactate levels, leading to lactic acidosis. To address lactic acidosis, PDACs robustly express monocarboxylate transporters (MCT1 and MCT4, encoded by SLC16A1 and SLC16A3, respectively) to coordinate glucose utilization and lactate mobilization (65, 84). Other glucose metabolism pathways are also altered in PDAC, such as the upregulation of the rate-limiting enzyme of the HBP, glutamine: fructose-6-phosphate amidotransferase-1 (GFPT1) (64). Many other mediators regulate glucose metabolism in pancreatic cancer cells. Under hypoxic conditions, hypoxia-inducible factor-1 (HIF-1) can promote glycolysis and upregulate the expression of HBP-related enzymes, such as GFPT2, an isoform of the HBP rate-limiting enzyme GFPT1 (63).

In a model of PDAC-CC, athymic mice injected with high-glycolytic MiaPaCa2 cells showed evidence of cachexia, such as weight loss, fat depletion, and muscle proteolysis (66), suggesting that glycolysis may be involved in PDAC-CC development. Glycolysis was associated with inefficient inter-organ substrate shuttles, as assessed by the lactate-to-pyruvate utilization ratio, LDH activity, and MCT1 expression, which was correlated with cachexia-related weight loss (63). The upregulation of GLUT1 and MCT1/4 promotes glucose utilization and improves the lactate-to-pyruvate utilization ratio in tumor tissue (63, 65). Paradoxically, OXPHOS, also known as the reverse Warburg effect, occurs in muscle, resulting in an increased lactate-to-pyruvate production ratio, providing a potential lactate supply for tumor use and supporting tumor progression and consequent atrophy (85). Additionally, the tumor secretes interferon-gamma (IFN-γ), which mediates the development of insulin resistance via reduced glucose and fatty acid [FA] uptake, leading to enhanced lipolysis in WAT (86). Inefficient inter-organ substrate shuttles are regarded as hallmarks of EOLT ( Figure 3 ).

Aerobic glycolysis occurs more commonly in tumor tissues than OXPHOS, which requires a sufficient oxygen supply, although OXPHOS is more efficient for ATP generation (30, 87). Nutrient depletion forces tumors to adapt by inducing nutrient scavenging mechanisms to support cancer progression, which can lead to CC (8, 9, 88). OXPHOS occurs in the mitochondria and is sensitive to stress conditions, as the respiratory complexes in stressed mitochondria produce high levels of reactive oxygen species (ROS) (62). Autophagy is a stress response induced by ROS to remove damaged mitochondria that overproduce ROS, promoting mitochondrial metabolism (89) ( Figure 2 : lower panel). In cachectic patients, increased OXPHOS and dysfunctional autophagy are associated with increased muscle wasting ( Figure 3 ) (90). Autophagy is an important proteolysis pathway activated during PDAC-CC and muscle wasting (91, 92).

Tumors supported by an adequate blood supply can perform aerobic metabolism and tend to exhibit the reverse Warburg effect. In tumors, aerobic metabolisms may utilize intermediates, such as lactate, to fuel the TCA cycle ( Figure 2 : lower panel), decreasing their dependence on glucose. The low uptake of glucose and the enhanced uptake of intermediate metabolites by tumors under aerobic conditions could protect these tumors from competing with hypoxic tumor regions (such as desmoplastic tumors) for glucose. In addition to OXPHOS, tumors able to perform aerobic metabolism can also utilize glutaminolysis as an alternative energy production pathway requiring activated mitochondrial metabolism (93). Glutamine is the most abundant and versatile nonessential amino acid (NEAA), found in both the blood and the cell cytoplasm, and can be used by both the glutamine-dependent pyruvate cycle and the TCA cycle (30, 94). In contrast, hypovascularization and desmoplasia often occur in PDAC; studies also found that HIF-1α (hypoxia-inducible factor-1α) stabilization promotes glycolytic enzymes to shift the metabolism by repressing OXPHOS (95, 96). Supposing that if the function of glycolysis is weakened, OXPHOS and glutamine-based processes will serve as alternative energy generation mechanisms in glucose-limited tumors (87) ( Figure 2 : lower panel).

Altered amino acid (AA) metabolism is a frequent feature in CC. Branched-chain amino acids (BCAA: leucine, isoleucine, and valine) act as important carbon sources and are useful for FA biosynthesis. High BCAA levels in plasma are associated with early PDAC and are often derived from increased protein breakdown in muscle and other body tissues ( Figure 3 ) (97, 98). The utilization of BCAAs by PDAC can result in plasma BCAA depletion during late-stage PDAC. Similar observations have been reported for glutamate, in which the plasma levels of glutamate and the glutamine/glutamate (Q/E) ratio are significantly reduced in cachectic patients and animal models compared with their healthy counterparts (83, 99). Glutamine metabolism is a primary source of nitrogen and carbon, contributing to macromolecular synthesis and redox balance (83). Glutaminase 1 (GLS1) converts glutamine to glutamate, after which glutamate dehydrogenase (GDH) catalyzes the conversion from glutamate to α-ketoglutarate (α-KG). However, GDH is repressed in PDAC, and cytoplasmic aspartate transaminase (GOT1) is upregulated (83) ( Figure 2 : lower panel). Cachexia is associated with more aggressive forms of PDAC, which may reflect the increased access of tumor cells to nutrients derived from protein breakdown and systemic changes in glucose metabolism (97, 100). Higher circulating BCAA levels may arise from the impaired catabolism of AAs that are commonly found in muscle ( Figure 3 ). Muscle wasting is characterized by decreased muscle mass, increased proteolysis, and reduced protein synthesis, changes which are mediated by the proteasome, nuclear factor kappa B (NF-κB), and the mammalian target of rapamycin (mTOR) pathways. The phosphoinositol 3-kinase (PI3K)/AKT/mTOR pathway is a nutrient-sensing mechanism stimulated by decreased glucose availability in the muscle. A higher mTOR activity induced by KRAS mutation in PDAC which is positively correlated to higher circulating BCAA levels (12). mTOR activation is responsible for the uptake of BCAA in tumor tissue. Circulating BCAA also can affect subcutaneous adipocyte AA dysmetabolism. Both NF-κB and AKT/mTOR signaling are involved in proteolysis. NF-κB regulates the ATP-dependent ubiquitin–proteasome proteolytic pathway, including muscle-specific E3 ubiquitin ligases (such as muscle atrophy F box protein [MAFbx/atrogin-1] and muscle RING finger–containing protein 1 [MuRF1]), which promote proteolysis and contribute to muscle atrophy (22). Cachexia is the end result of convergent metabolic adaptations induced by tumors to satisfy their metabolic requirements.

In addition to glucose and amino acid metabolism, metabolic alterations in cachexia can include lipid metabolism. Approximately 93% of triacylglycerol FAs used by tumors are synthesized de novo by the mitochondria and cytosolic acetyl coenzyme A (CoA). Enzymes that participate in de novo FA and cholesterol synthesis are upregulated in PDAC, such as FA synthase (FASN) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Under pancreatic inflammatory conditions, wasting adipocytes release FAs into the plasma, increasing plasma concentrations of saturated (SFAs), monounsaturated (MUFAs), and polyunsaturated FAs (PUFAs) (101). SFAs and MUFAs promote PDAC progression (102). However, a study performing transcriptomics and metabolomics suggested that lipase and a panel of FAs were significantly decreased in PDAC, and the presence of two SFAs (palmitate and stearate) inhibited tumor cell proliferation (103). Therefore, the roles played by FAs in PDAC appear complicated and remain unclear. PDAC patients present with distinct phenotypes associated with cachexia development, such as adipose tissue loss prior to skeletal muscle wasting or the loss of adipose tissue alone (104). A recent report indicated that soft tissue changes are initiated in PDAC before skeletal muscle loss (19), and the significant loss of visceral adipose tissue has been observed in PDAC-CC (18). In a retrospective cohort study, PDAC-CC was associated with the accumulation of oleic acid in plasma, resulting from malnutritional compensatory mechanisms triggered by the lack of oleic acid uptake into tissue (105). In a pre-cachexia model, increased FA oxidation occurs before muscle mass reduction, suggesting that FA may serve as a dominant energy source in PDAC-CC (18, 106). Adipose tissue lipolysis contributes to circulating FAs and subsequent FA uptake and lipid accumulation in the muscle and tumor tissue, leading to eventual metabolic derangement and muscle wasting after a period of metabolic adaptation. Several lipolytic enzymes are elevated, such as adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), further suggesting the occurrence of enhanced lipolysis. Increased ATGL and HSL activity correlate with tumor growth and WAT loss in cachexia (107) ( Figure 3 ). Tumor progression is also associated with the shift from WAT to BAT, known as adipose tissue browning. BAT is a metabolic hallmark mediated by uncoupling protein 1 (UCP-1). In KPC and Kras^LSLG12D/+Trp53^f/f mice, adipose tissue browning is associated with increased UCP-1 expression and occurs prior to the onset of fat wasting, consistent with clinical observations (108). A few studies have suggested that fat loss is an early and precipitating event prior to muscle loss in PDAC-CC, even in the absence of muscle wasting (18, 19, 21, 33, 104, 105, 107). Clinical studies suggested that fat loss may serve as a driving force for cachexia mortality, emphasizing the important roles of adipocytes in PDAC-CC and supporting the need to monitor adipose in patients with CC (20, 21).

Tumors hijack organ and tissue function, causing muscle and adipocyte wasting. Enhanced glycolysis in tumors and the upregulation of lipolysis and proteolysis in wasting tissue counterbalance the reductions in muscle and fat under cachectic conditions ( Figure 3 ). Wasting muscle and adipocytes are among the convergent metabolic adaptations induced by tumors to satisfy their metabolic requirements. Patients with PDAC and PDAC-CC exhibit distinct and heterogeneous metabolic changes. Tumor, muscle, and adipocyte tissues all act as endocrine organs involved in the regulation of metabolic homeostasis, consistent with the EOLT hypothesis. In addition to metabolic alterations, bi-directional feedback occurs between tumor tissues and other organs, driven by the oncogenes and mediators (8, 12, 21, 32, 62).

Endocrine organs and cells synthesize biologically active compounds that are released directly into the circulation and interact with other cells. Cachexia-associated inflammation is influenced by numerous bioactive molecules, such as TNFα, IL-1, IL-6, and IL-8 ( Table 5 and Figure 5 ). Cachexia-affected organs can act as autocrine or paracrine organs, releasing factors into the bloodstream to promote systemic crosstalk. These cytokines have multifactorial effects, triggering a hypercatabolic feedforward loop between the tumor, adipose tissue, and muscle mediated by the NF-κB and Janus kinase (JAK)/STAT pathways (29, 174, 175) ( Figure 5 ). NF-κB and JAK/STAT activation enhance lipolysis, downregulate lipogenesis, and stimulate the catabolism of lean body mass (12).

A salient feature that distinguishes PDAC from other KRAS-mutant cancers is an extensive fibro-inflammatory stroma, which accounts for 80%–85% of the tumor bulk. These stromal cells are recruited and reprogrammed by PDAC cells during cancer progression and cachexia development. Secreted factors ( Table 5 ) enable these cells to communicate with PDAC, creating a dynamic feedback circuit associated with intrinsic KRAS signaling in PDAC cells ( Figure 5 ).

Various circulating pro-inflammatory cytokines have been implicated in PDAC-CC, including IL-6, IL-1, IL-8, TGF-β, and TNFα …etc (detailed in Table 5 ) (12, 21, 29, 123). These cytokines likely derive from various sources and result in systemic effects (123, 176). Oncogenic RAS drives the expression of multiple inflammatory cytokines, including IL-1 and IL-6 (21, 146). Inflammatory cytokines released by tumor cells may be prominent cachexia-associated factors that regulate autocrine and paracrine function, promoting tumor progression and cachexia development. For example, IL-6 plays autocrine roles in supporting tumorigenesis in vivo and induces weight loss and inflammation in cachexia via a paracrine manner (21, 68, 152). Other cytokines, such as IL-1, IL-8, TNFα, and INF-γ, have also been associated with weight loss and poor survival in PDAC (148, 177, 178). TNF-α and IL-1 can induce anorexia, producing both hypercatabolic and anorexigenic effects ( Figures 1 and 5 ). Circulating IL-1β promotes NF-κB activation in the hypothalamus, enhancing glucocorticoid production and resulting in catabolic effects in both muscle and adipose tissue. TGF-β1 can induce proteolysis through the E3 ligase atrogin-1 in animal models. TGF-β inhibition improved muscle wasting in the KPC model (129). Activin A and myostatin belong to the TGF-β superfamily and are associated with muscle wasting through the activation of the Smad2/3 pathway, which decreases AKT–mTOR-mediated protein synthesis and enhances ubiquitin ligase–mediated proteolysis (18, 128). These cytokines drive diverse catabolic processes across multiple cells and organs, forming a catabolic feedforward loop ( Figure 1 ).

In muscle tissue, the JAK–STAT and NF-κB pathways are the dominant catabolic pathways activated by circulating IL-6 and TNFα in muscle wasting (174). IL-6 induces NF-κB activation, which can also upregulate ubiquitin-mediated proteasomal degradation in wasting (179). Proteolysis is a prerequisite for muscle wasting, and both lipolysis and adipopenia may occur prior to muscle loss. Lipolysis results in increased circulating FFAs, triggering the secretion of Atrogin-1 and MuRF1, which induce muscle atrophy.

In adipocytes, lipolysis plays a substantial role in increasing the catabolism of stored fat. ATGL and HSL act to reduce fat to its component FAs, leading to the loss of body mass. Secreted IL-6 can trigger browning by inducing UCP-1 expression in adipocytes (18, 180). The catabolic effects of IL-6 on WAT in vitro are mediated through the JAK/STAT3 and NF-κB pathways (21, 181).

Genetic instability and epigenetic changes are both involved in pancreatic oncogenesis and cachexia development ( Table 6 ). Recently, miRNAs, small non-coding RNAs 19–25 nucleotides in length, have been identified in an increasing number of biological processes, including KRAS signaling and the JAK–STAT, PI3K–AKT, notch, and TGF-β signaling pathways ( Figure 6A ). These influences contribute to the control of several cancer-related processes in PDAC, such as tumor growth, apoptosis, metastasis, drug resistance, and the immune response. In addition to roles in oncogenesis and tumorigenesis, aberrant miRNA expression may affect cytokine production or directly alter metabolic processes, resulting in a metabolism remodeling that facilitates PDAC progression and cachexia development (see Figure 6 and Table 6 ).

Recent studies have detected miRNAs in serum, plasma, tissue, and tumors ( Table 6 ). Studies indicates that miRNAs are commonly found in various EVs, such as exosomes, apoptotic bodies, microvesicles (MV), and lipoproteins, allowing them to target cells and contribute to intercellular signaling through endocrine, paracrine, and autocrine pathways (182, 183, 198, 199, 215–217). Losses in muscle proteins and fat mass are the most important signatures of cachexia and can result in the generation of microvesicles containing miRNAs (see Figure 6B : bottom panel). Most studies have identified miRNAs expressed in tumor cells; however, some miRNAs are tissue‐specific or tissue‐enriched, involved in either the active or passive stimulation of metabolic changes and inflammatory responses ( Table 6 ). In PDAC-CC, miR-21, miR221/222, miR27a and miR155 are commonly correlated with muscle and adipocyte wasting through the transcription E3 ubiquitin ligases (mediated by FoxO3 or FoxO1 in muscle), JUN–STAT3, or TGF-β; ( Figure 6B : bottom panel). Given the roles of miRNAs in gene expression and the regulation of inflammatory responses and metabolic reprogramming, additional study of miRNAs remains necessary. An ongoing observational trial (NCT05275075) aims to analyze the miRNA profiles in patients with PDAC-CC. The causal roles of miRNAs and molecular mechanisms in cachexia remain under debate and require further discussion and study; however, therapeutic approaches for modifying multiple targets have been suggested (218, 219). The study of miRNAs could also contribute to the development of diagnostic or prognostic biomarkers and new targets for cachexia prevention or treatment.