Wei Huang
Wei Sun2†
Ziliang Wang- 1Science and Technology Innovation Center, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- 2Department of Gynecology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Cisplatin remains a cornerstone of chemotherapy for numerous cancers, despite the persistent challenges of toxicity and the development of drug resistance. Therefore, a deeper understanding of the mechanisms behind cisplatin resistance and the development of strategies to counter it are of critical importance. This review systematically examines the pivotal role of mitochondrial dynamics in cisplatin resistance and discusses emerging therapeutic strategies that target these processes. Mitochondrial dynamics regulate the structure and function of the mitochondrial network through a balance of fusion and fission. Dysregulation of this process directly contributes to cisplatin resistance by maintaining cellular energy homeostasis, inhibiting apoptosis, and enhancing oxidative phosphorylation (OXPHOS). Furthermore, mitophagy, metabolic reprogramming, and the tumor immune microenvironment converge on mitochondrial dynamics to drive the acquisition of drug resistance. Consequently, targeting mitochondrial dynamics presents a promising approach to overcome cisplatin resistance. Potential strategies include restoring the balance of fusion and fission, intervening in mitophagy, disrupting OXPHOS metabolism, and developing mitochondrial-targeted nanodrug delivery systems. However, despite this promising outlook, significant challenges remain, including the heterogeneity of resistance mechanisms, a lack of reliable biomarkers, and the need for selective targeting to minimize off-target effects.
1 Introduction
Mitochondrial dynamics refer to the dynamic changes in the morphology, distribution, and function of the mitochondrial network. This process is centrally governed by the balanced regulation of fission and fusion. In essence, it encompasses the temporal evolution of the network’s morphological features and connectivity, achieved primarily through the continual structural remodeling driven by these two opposing mechanisms (1). Mitochondrial fission is the process by which elongated tubular mitochondria are divided into separate organelles. This process is primarily mediated by proteins such as MFF and Drp1 (2). The Drp1 protein facilitates mitochondrial fission by forming helical structures that constrict and sever the mitochondrial outer membrane, a process powered by GTP hydrolysis (3). In contrast, mitochondrial fusion is the process by which separate mitochondria merge to form elongated, branched, and interconnected tubular networks. This event is orchestrated by the coordinated actions of the outer membrane proteins Mfn1 and Mfn2, and the inner membrane protein OPA1 (4, 5). The overall morphology of the mitochondrial network is determined by the dynamic balance between fission and fusion. An excess of fission results in a fragmented network, while a predominance of fusion promotes a highly interconnected morphology (6). Mitochondrial fission facilitates network fragmentation by isolating damaged mitochondrial components for removal via mitophagy (7), This adaptive shift promotes glycolysis in cancer cells (8). Mitochondrial fusion enables functional complementation by diluting damaged components, such as mutated mitochondrial DNA (mtDNA), thereby helping to maintain overall mitochondrial functional integrity (4). Furthermore, the formation of an interconnected network through fusion enhances the efficiency of cellular oxidative phosphorylation (6). Furthermore, the formation of an interconnected network through fusion enhances the efficiency of cellular oxidative phosphorylation (6). In summary, mitochondrial dynamics serve as a crucial mechanism for maintaining cellular homeostasis. The precisely regulated balance between fission and fusion enables cells to remodel organelle morphology, control quality, and adapt energy production to meet metabolic demands. Dysregulation of this process is strongly implicated in the pathogenesis of diverse diseases, including neurodegenerative disorders, metabolic diseases, and cancer. Consequently, developing targeted therapeutic interventions against key regulators of mitochondrial dynamics, such as the proteins Drp1 and Mfn2, has become a major focus of current research (9, 10).
Cisplatin is a chemotherapeutic agent extensively used in the treatment of various solid tumors. Nevertheless, its clinical efficacy is substantially limited by the development of drug resistance and tumor recurrence (11–13). Nevertheless, cisplatin-based combination chemotherapy can achieve curative outcomes in highly sensitive malignancies, such as testicular cancer. Research indicates that clinical response rates to cisplatin vary substantially across different cancer types. For instance, response rates to cisplatin are as low as 20% in non-small cell lung cancer (NSCLC) (14), In contrast, response rates exceed 90% in testicular cancer (15). The mechanisms underlying cisplatin resistance are highly heterogeneous. Firstly, the overexpression of ABC transporter proteins—such as ABCB1/P-gp, ABCC1, and ABCG2—can mediate cisplatin efflux from cells, thereby contributing to multidrug resistance (MDR). This mechanism is particularly enriched in cancer stem cells (CSCs) (16, 17). In mesothelioma stem cells, activation of ABCB5 has been identified as a key mediator of cisplatin resistance (18). Furthermore, dysregulation of DNA repair mechanisms represents another major pathway. Tumor cells can counteract cisplatin-induced DNA damage by enhancing their repair capacity. For instance, in nasopharyngeal carcinoma, overexpression of FOX family transcription factors such as FoxM1 and FOXQ1 promotes this protective response (16). Additionally, inhibition of apoptosis significantly contributes to cisplatin resistance. This can occur through overexpression of anti-apoptotic proteins such as Bcl-2 and Bcl-xL, which suppress cisplatin-induced cell death. Alternatively, loss of pro-apoptotic function, as seen with dysfunctional mutant p53 in gastric cancer, also confers treatment resistance (19);In nasopharyngeal carcinoma, TBL1XR1 contributes to resistance by activating the NF-κB signaling pathway, which subsequently inhibits apoptosis (16). Epigenetic regulation also plays a significant role; non-coding RNAs (ncRNAs), such as lncRNA HOTAIR and circCCND1, promote resistance through multiple mechanisms including the modulation of reactive oxygen species (ROS) levels, the enhancement of cancer stem cell properties, and the facilitation of DNA repair processes (20). Dysregulation of miRNAs, such as the downregulation of miR-149-3p, can enhance cisplatin resistance in lung cancer by targeting genes like TMPRSS4 (21, 22). Within the tumor microenvironment (TME), the epithelial-mesenchymal transition (EMT) process—for instance, Snail-induced reduction of E-cadherin—can enhance P-gp function and promote drug efflux (17). Autocrine signaling loops, such as the Wnt/IL-1β/IL-8 pathway, can induce ABCB5 expression in mesothelioma stem cells (18). Regarding metabolic and stress adaptations, endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) have been linked to platinum resistance in high-grade serous ovarian carcinoma (HGSOC) (23). Mitophagy exhibits a dual regulatory role in drug resistance in liver cancer: pro-survival mitophagy enhances chemoresistance, whereas pro-death mitophagy suppresses tumor growth (24). To address cisplatin resistance, current strategies primarily involve combination therapies, including targeted agents, epigenetic modulators, and immunotherapy. For example, in drug combinations, PARP inhibitors are used synergistically with cisplatin to exacerbate DNA damage in tumor cells. However, such approaches still face challenges related to safety, such as off-target effects and the risk of viral reactivation (25). In epigenetic interventions, exosome-mediated delivery of siRNA (e.g., targeting the CPT1A gene) has shown potential to reverse cisplatin resistance in gastric cancer, though optimization of delivery efficiency and targeting specificity remains necessary (26). In immunotherapy, immune checkpoint inhibitors (ICIs) demonstrate efficacy in certain tumors; however, their utility is complicated by complex resistance mechanisms, such as T-cell dysfunction (16). In summary, cisplatin resistance remains a formidable obstacle in cancer therapy, arising from highly complex and multifactorial biological processes. Current research efforts are primarily focused on developing combination strategies involving targeted therapy, epigenetic modulation, and immunotherapy. However, significant challenges persist, including the inherent complexity of resistance mechanisms, a scarcity of reliable biomarkers, and difficulties in clinical translation.
Mitochondria play multifaceted roles in cellular physiology, functioning not only as the primary site of energy metabolism but also as key regulators of drug tolerance. Under hypoxic conditions, reduced oxidative damage to mtDNA confers enhanced resistance to cisplatin in tumor cells (27). Furthermore, the upregulation of mitochondrial apurinic/apyrimidinic endonuclease (mtAPE1) in osteosarcoma-resistant cells contributes to chemoresistance by clearing oxidatively damaged mtDNA and suppressing ROS production, thereby protecting cells from cisplatin-induced cytotoxicity (28). Collectively, these findings highlight an essential link between mtDNA damage repair mechanisms and cisplatin resistance in cancer cells. Therefore, mitochondrial-targeted strategies show significant potential for overcoming cisplatin resistance. For example, drug delivery systems designed to target mitochondria—such as those using nanoparticles or liposomes to transport cisplatin directly to these organelles—can bypass the nuclear DNA repair mechanisms that often confer drug resistance (29). In summary, mitochondria contribute to cisplatin resistance through a spectrum of mechanisms that exhibit distinct tumor-type specificity and microenvironmental dependencies. Consequently, mitochondrial-targeted interventions represent a promising strategic avenue for effectively reversing cisplatin resistance.
2 The mechanistic role of key mitochondrial dynamics regulators in cisplatin resistance
2.1 Imbalance between fusion and fission
A marked correlation exists between mitochondrial dynamics and cisplatin resistance. In cisplatin-resistant cells, the upregulation of key fusion proteins Mfn1, Mfn2, and OPA1 promotes mitochondrial elongation. This morphological alteration helps maintain cellular energy homeostasis and effectively imparts resistance to apoptosis (30, 31). Investigations in non-small cell lung cancer have revealed that mitochondrial fusion, mediated by the p32/OPA1 axis, directly promotes cisplatin resistance (32). In lung adenocarcinoma, elevated OPA1 expression similarly enhances cisplatin resistance by inactivating the caspase-dependent apoptotic pathway (33). In tongue squamous cell carcinoma (TSCC), mitochondrial fission factor (MFF) mediates both mitochondrial fission and apoptosis following cisplatin treatment. During this process, miR-593-5p expression is downregulated. Further investigation revealed that miR-593-5p targets the 3’ untranslated region (3’UTR) of MFF mRNA to suppress its translation, consequently attenuating both mitochondrial fission and cisplatin sensitivity (34). In cholangiocarcinoma cells, cisplatin-induced INF2 protein is degraded through both SEC62-mediated reticulophagy and the ubiquitin-proteasome system. This degradation impairs mitochondrial fission, resulting in a hyperfused mitochondrial network. This adaptive response has been identified as a key mechanism by which cholangiocarcinoma (CCA) cells resist cisplatin-induced apoptosis (35). Furthermore, Drp1 is a conserved mechanoenzyme that catalyzes mitochondrial constriction and fission through GTP hydrolysis, serving as a master regulator of mitochondrial division (36, 37). Studies demonstrate that cisplatin-resistant ovarian cancer cells exhibit significantly lower DRP1 expression levels and more pronounced mitochondrial fusion compared to their cisplatin-sensitive counterparts. This shift in mitochondrial dynamics confers increased resistance to cisplatin-induced apoptosis (38). Collectively, these findings indicate that mitochondrial fusion is a significant contributor to cisplatin resistance in cancer cells. However, other studies have reported an upregulation of the MFF in cisplatin-resistant liver cancer cells. In this context, MFF enhances chemoresistance by activating Drp1 to promote mitochondrial fission, suggesting that the mechanisms of resistance may be cell type-specific (39). Research further indicates that extracellular matrix (ECM) stiffness influences mitochondrial ROS production and NRF2 activation through the regulation of DRP1. Softer ECM promotes perimitochondrial F-actin assembly, which enhances DRP1-mediated mitochondrial fission. This fission process is coupled with increased mtROS generation, leading to NRF2 pathway activation and subsequent augmentation of cellular antioxidant defense systems. Consequently, soft ECM conditions activate both NRF2 and DRP1 signaling, enabling cancer cells to develop resistance to ROS-dependent chemotherapeutic agents, including cisplatin and arsenic trioxide (40). Therefore, mitochondrial fusion and fission processes exhibit a dual role in regulating cisplatin resistance. Nevertheless, it is evident that an imbalance between mitochondrial fusion and fission is directly linked to the development of cisplatin resistance (Table 1).
Table 1. Summary of key mitochondrial dynamics proteins and their functions in cisplatin resistance.
2.2 The Janus-faced nature of mitophagy
The process of mitophagy plays a crucial role in regulating mitochondrial quality control and thereby helping to maintain normal cellular physiological functions (41–43). As two essential components of a unified mitochondrial quality control system, mitophagy and mitochondrial dynamics work in concert to preserve the integrity of the mitochondrial network and maintain cellular energy homeostasis (44). Mitochondrial dynamics and mitophagy collaboratively establish a quality surveillance network through the fission-fusion cycle and functional interactions among key proteins, including Drp1, Mfns, and the PINK1/Parkin pathway. Mitochondrial fission facilitates the isolation and subsequent autophagic removal of damaged organelles, whereas fusion enables content mixing to repair mild damage and prevent excessive mitochondrial turnover. Disruption of the fission-fusion equilibrium induces mitochondrial dysfunction, which contributes to cancer pathogenesis and is strongly associated with the development of cisplatin resistance (45–47). Elucidating the molecular mechanisms underlying mitophagy in cisplatin resistance is therefore crucial for understanding mitochondrial dynamics.
Mitophagy also exhibits a dual role in mitochondrial-mediated cisplatin resistance, with its effects being highly context-dependent based on factors such as cell type, physiological state, and regulatory intensity. On one hand, in cisplatin-treated malignant cells, the mitophagy mechanism promotes cell survival by clearing damaged mitochondria. This process reduces the accumulation of ROS and alleviates mitochondrial dysfunction, thereby helping cancer cells evade apoptosis. In NSCLC cells, for example, Caveolin-1/Parkin-mediated mitophagy enhances cisplatin resistance. Conversely, inhibiting mitophagy restores drug sensitivity and promotes apoptosis (48). Similarly, in ovarian cancer cells, cisplatin treatment activates the ERK signaling pathway to induce mitophagy as a compensatory mechanism to counteract its toxicity. Pharmacological inhibition of this autophagic response consequently enhances the cytotoxic effects of cisplatin (49). Conversely, excessive activation of mitophagy may lead to the unchecked removal of functional mitochondria, subsequently triggering metabolic dysregulation and energy exhaustion that ultimately induce cell death. This is supported by studies showing that hyperactive mitophagy disrupts cellular metabolic homeostasis, thereby promoting cell death (50). In hepatocellular carcinoma cells, ketoconazole promotes cisplatin-induced apoptosis by downregulating COX-2 to induce mitophagy (51). Collectively, these findings substantiate the dual role of mitophagy in the development of cisplatin resistance. At moderate levels, mitophagy clears damaged mitochondria to maintain cellular viability, thereby promoting resistance. Conversely, excessive mitophagic activity can disrupt cellular homeostasis and paradoxically enhance the cytotoxic efficacy of cisplatin (Figure 1).
Figure 1. The dual role and underlying mechanisms of mitophagy in cisplatin resistance.
2.3 Mitochondrial dynamics and cancer stemness
CSC possess intrinsic resistance mechanisms that enable them to evade cisplatin-induced cytotoxicity through pathways such as ROS scavenging and activation of anti-apoptotic signaling. This phenomenon has been observed in multiple cancer types, including ovarian cancer, mesothelioma, and nasopharyngeal carcinoma (18, 52, 53). However, mitochondrial morphological changes show a significant correlation with the maintenance of cancer stemness. In oral squamous cell carcinoma (OSCC), inhibition of the fission protein DRP1 induces mitochondrial elongation. This morphological change increases α-ketoglutarate (α-KG) levels, which promotes histone H3K27me3 demethylation. Consequently, this epigenetic modification downregulates the expression of stemness-related genes (e.g., SNAI2) and EMT programs, ultimately attenuating CSC properties (54). Research in brain tumor-initiating cells (BTICs) has demonstrated that hyperactivation of DRP1 induces mitochondrial fragmentation. This fragmentation is closely associated with enhanced self-renewal capacity, drug resistance, and invasiveness in CSCs. For instance, in lung CSCs, FIS1-mediated fission promotes mitophagy, thereby helping to maintain stemness properties (55, 56). These findings reveal that the effects of mitochondrial fusion and fission on cancer stemness exhibit context-dependent heterogeneity across tumor types. They further confirm the bidirectional regulatory role of mitochondrial dynamics in mediating cisplatin resistance.
Mitochondrial metabolism plays a pivotal role in maintaining the stemness properties of tumor cells. CSCs predominantly rely on mitochondrial OXPHOS rather than glycolysis. In CSCs derived from ovarian cancer, small cell lung cancer, and glioma, key enzymes involved in OXPHOS and fatty acid oxidation (FAO) are upregulated, providing essential metabolic support that meets their high energy demands and enhances drug resistance (57, 58). This underscores the essential role of mitochondrial metabolism in providing the energy required to maintain tumor cell stemness. However, elongated mitochondrial morphology promotes glutamine metabolism—mediated by the ASCT2 transporter—to fuel the tricarboxylic acid (TCA) cycle, while simultaneously suppressing the expression of stemness-related genes through epigenetic regulatory mechanisms (54). These findings reveal the mechanistic role of mitochondrial dynamics in regulating metabolic processes to maintain cancer stemness. Furthermore, mitochondrial retrograde signaling—a process studied in epigenetics and signal transduction—can trigger cell reprogramming resembling EMT, thereby enhancing cellular migration and invasion capabilities (59). Furthermore, activation of DRP1 during mitochondrial fission regulates stem cell differentiation fate by modulating the FOXO/Notch signaling pathway (60).
Mitochondrial dynamics play a central role in apoptosis resistance; a mechanism closely linked to the therapeutic sensitivity of cancer stem cells. According to relevant studies, the regulation of mitochondrial dynamics significantly influences the therapeutic response of cancer stem cells. Inhibition of DRP1 expression induces mitochondrial elongation, thereby enhancing the sensitivity of OSCC to the ferroptosis-inducing agent erastin (54). Therefore, modulating mitochondrial dynamics can influence the sensitivity of cancer stem cells to ferroptosis inducers, ultimately affecting therapeutic efficacy. Moreover, the fused mitochondrial state also influences cell death resistance in cancer stem cells. Overexpression of MFN2 promotes mitochondrial fusion, thereby conferring resistance to apoptosis, whereas mitochondrial fission facilitates the apoptotic process (61, 62). However, during chemotherapy, mitochondrial fragmentation may paradoxically enhance cell death resistance in certain cancer cells. This paradox highlights the context-dependent dual role of mitochondrial dynamics regulation in cancer therapy. Furthermore, CSCs can dynamically modulate mitochondrial morphology to develop resistance against OXPHOS inhibitors. For example, in acute myeloid leukemia, cancer stem cells can acquire resistance to OXPHOS inhibitors through exogenous mitochondrial transfer. This adaptive mechanism demonstrates how cancer stem cells dynamically modulate both mitochondrial structure and function to counteract therapeutic stress, thereby maintaining their survival and proliferative capacity (63).
3 Drug resistance mechanisms through metabolic-dynamic interplay
3.1 The interplay between mitochondrial dynamics and metabolism
Mitochondrial dynamics are intimately and inextricably linked to tumor cell metabolic processes, directly regulating cellular energy metabolism. Studies demonstrate that mitochondrial fusion enhances OXPHOS efficiency, with fused mitochondria exhibiting superior energy production capacity. Conversely, excessive mitochondrial fission can induce fragmentation of metabolic processes, ultimately disrupting normal cellular function (64–67). Cellular metabolic status can conversely regulate mitochondrial dynamics. High-glucose or high-lipid environments promote mitochondrial fission, leading to increased production of ROS. This process may ultimately disrupt cellular metabolic homeostasis (68, 69). Furthermore, GLUT4 and PGC-1α—a transcriptional co-regulator of mitochondrial genes—coordinate cellular metabolic adaptation by modulating the activity of dynamics proteins such as OPA1 (70, 71). The interactions between these molecules and proteins collectively form an intricate interrelationship between mitochondrial dynamics and tumor cell metabolism, thus holding critical scientific importance for deepening our understanding of tumorigenesis and cancer progression. In drug-resistant cancer cells, mitochondrial fusion is markedly enhanced, a process primarily underpinned by upregulated expression of mitofusin 1 and 2 (Mfn1/2). This fusion process facilitates the formation of a highly interconnected mitochondrial network, which markedly enhances cellular OXPHOS capacity. This improved bioenergetic competence enables cells to more effectively respond to environmental stressors and meet internal metabolic demands (31). Furthermore, perturbations in lipid metabolism—such as enhanced fatty acid oxidation—may further promote mitochondrial fusion through the regulatory activity of key transcription factors including sterol regulatory element-binding factor 1 (SREBF1). This adaptive response helps safeguard stable energy supply under adverse environmental conditions (72, 73). This intricate interplay between metabolic and dynamical regulatory mechanisms provides a crucial biological foundation for tumor cell survival and drug resistance (Figure 2).
Figure 2. Cisplatin resistance mediated by the interplay between mitochondrial dynamics and metabolism.
3.2 The metabolic-dynamic axis mediates drug resistance
In cancer cells, metabolic reprogramming not only alters the ways in which cells acquire and utilize energy but also profoundly impacts mitochondrial dynamics (74, 75). In cisplatin-resistant tumor cells, metabolic reprogramming occurs in response to drug-induced stress, characterized by reduced reliance on glycolysis and increased dependence on OXPHOS and fatty acid oxidation for energy production (76, 77). This metabolic shift necessitates corresponding structural and functional adaptations in the mitochondrial network to meet increased energy demands. Specifically, drug-resistant cells enhance their mitochondrial infrastructure through increased biogenesis and functional optimization, thereby supporting the efficiency of both OXPHOS and fatty acid oxidation processes (78). Furthermore, cisplatin-resistant cells typically persist in environments characterized by elevated levels of ROS (79). ROS are oxidizing molecules generated during cellular metabolism. Under normal physiological conditions, they function as signaling molecules; however, when produced in excess, ROS induce oxidative stress and cause cellular damage (80). To adapt to high ROS conditions, drug-resistant cells trigger mitochondrial fusion, resulting in enlarged mitochondria. This morphological adaptation enhances the mitochondrial antioxidant defense capacity, thereby protecting cells from oxidative damage (81). Furthermore, cisplatin-resistant cells activate additional antioxidant pathways, such as through the upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), to bolster their antioxidant defense systems. Together, this antioxidant response and mitochondrial fusion create a cooperative resistance cycle that not only counteracts drug toxicity but also sustains cell viability (80, 82) (Figure 3). From an immunotherapy perspective, enhanced OXPHOS contributes to EMT, which in turn upregulates programmed death-ligand 1 (PD-L1) expression levels (78). The upregulation of PD-L1 sensitizes otherwise immunotherapy-resistant tumor cells to immune treatment, thereby enhancing its efficacy. However, it is important to note that this beneficial effect of OXPHOS enhancement is accompanied by certain negative consequences, as it simultaneously equips tumor cells with enhanced evasion mechanisms that effectively bypass the cytotoxic effects of chemotherapeutic agents such as cisplatin (78, 83). Thus, while the efficacy of immunotherapy is enhanced, the effectiveness of chemotherapeutic agents may be significantly compromised, presenting a novel therapeutic challenge in oncology. In summary, mitochondrial dynamics play a pivotal role in cell survival by maintaining metabolic homeostasis through fine-tuned regulation of processes such as OXPHOS efficiency and ROS balance, ultimately exerting profound effects on cellular viability (84, 85). The imbalance in mitochondrial dynamics—characterized by enhanced fusion and suppressed fission—is closely associated with cellular metabolic reprogramming during the development of cisplatin resistance. This metabolic reprogramming manifests as increased cellular dependence on OXPHOS and enhanced lipid metabolism. Collectively, these adaptations enable cells to counteract cisplatin’s cytotoxic effects, thereby promoting survival during chemotherapy (86). Therefore, a thorough investigation of mitochondrial dynamics and their interplay with metabolic reprogramming is of critical importance for elucidating the mechanisms of cisplatin resistance and developing novel therapeutic strategies.
Figure 3. Mitochondrial dynamics affects cell metabolism to form a drug-resistant cycle.
4 The crosstalk between immunity and mitochondrial dynamics in drug resistance
4.1 The tumor immune microenvironment and cisplatin resistance
Cisplatin is a cornerstone chemotherapeutic agent whose efficacy is significantly limited by the development of drug resistance. It is well established that resistance arises not only from cell-intrinsic mechanisms but also through an orchestrated collaboration with the tumor immune microenvironment (TIME).The TIME constitutes a dynamic network composed of immune cells, stromal cells, soluble factors, and the extracellular matrix. Through bidirectional crosstalk with tumor cells, it co-fosters a protective niche that favors therapeutic failure (87). A key underlying mechanism involves tumor-associated macrophages (TAMs). Under the pressure of cisplatin, these cells polarize towards an M2-like, pro-tumoral phenotype. These M2-like TAMs secrete factors such as interleukin-6 (IL-6), which in turn activate anti-apoptotic pathways, including STAT3, within tumor cells. This cascade ultimately blunts cisplatin-induced cell death (88). Of particular importance is the finding that TAM-derived cathepsin B can directly inactivate cisplatin in the extracellular compartment, thereby effectively diminishing the drug’s availability and subsequent intracellular accumulation (89). Furthermore, myeloid-derived suppressor cells (MDSCs) represent another pivotal player. They upregulate the expression of immunosuppressive products such as arginase-1 (ARG-1), inducible nitric oxide synthase (iNOS), and ROS. This activity suppresses the function of cytotoxic T cells and depletes CD8+ T cells, thereby compromising the immune system’s capacity to clear drug-damaged tumor cells (90). Furthermore, cancer-associated fibroblasts (CAFs) contribute to resistance by remodeling the extracellular matrix (ECM) to create a physical barrier that impedes drug penetration, and by delivering pro-survival molecules such as miR-21 via exosomes to directly regulate apoptotic pathways within tumor cells (91). Moreover, this resistant microenvironment is further consolidated by the cisplatin-induced upregulation of PD-L1 and the immunosuppressive activity of regulatory T cells (Tregs) (92). In summary, current research unequivocally positions the TIME as a central driver of cisplatin resistance. The intricate crosstalk between these immune cells and tumor cells ultimately leads to downstream effects that collectively converge to reprogram the core fate-determining processes of tumor cells: namely, cellular metabolism and survival signaling. Notably, the research frontier is beginning to reveal that this microenvironment-mediated resistance is, in large part, executed through the regulation of tumor cell mitochondrial function (93, 94). The secretory and interactive signals from immune cells converge to rewire the mitochondrial biology, metabolism, and death susceptibility of cancer cells, constituting the ultimate defense against cisplatin. This convergence thereby unveils a mitochondria-centric axis for both understanding and therapeutically overcoming this resilience.
4.2 Cisplatin resistance orchestrated by the tumor immune microenvironment and mitochondrial dynamics
The function of immune cells within the tumor microenvironment is often regulated by their own mitochondrial dynamics, which in turn indirectly modulates the therapeutic efficacy of cisplatin. Under the hypoxic and acidic conditions of the tumor, both tumor-infiltrating lymphocytes (TILs) and natural killer (NK) cells frequently exhibit excessive mitochondrial fission, thereby promoting their functional exhaustion. PD-1 signaling can suppress this fission process, aiding T cells in maintaining metabolic fitness (6). This reveals that an imbalance in mitochondrial dynamics can impair the tumor-clearing capacity of immune cells, thereby indirectly sheltering cancer cells from chemotherapeutic attack by agents such as cisplatin. Similarly, related studies indicate that bone marrow-derived mesenchymal stem cells (MSCs) can promote chemoresistance in T-cell acute lymphoblastic leukemia (T-ALL) cells by influencing the extracellular signal-regulated kinase (ERK) pathway. This leads to the activating phosphorylation of Drp1 at serine 616 (S616), which in turn drives mitochondrial fission and enhances the drug tolerance of the cancer cells (95). Research in colorectal cancer has revealed that high-mobility group box 1 (HMGB1), engaging its receptor RAGE, activates the ERK1/2 pathway to phosphorylate and activate Drp1, thereby fostering chemoresistance. This pathway is further supported by the association between the RAGE-G82S polymorphism and a hyperphosphorylated state of Drp1 at Ser616 in the tumor microenvironment, highlighting the relevance of Drp1 phosphorylation and immune interactions in mediating cisplatin resistance (96). In hepatocellular carcinoma, Drp1-mediated mitochondrial fission triggers mitochondrial DNA (mtDNA) stress, which promotes the recruitment and polarization of tumor-associated macrophages (TAMs). Furthermore, high Drp1 expression in tumor cells shows a significant positive correlation with TAM infiltration in HCC tissues (97). Collectively, these results not only identify mitochondrial fission as a key driver of TAM infiltration but also imply a potential mechanism by which immuno-metabolic crosstalk, governed by mitochondrial dynamics, contributes to chemoresistance against agents like cisplatin.
5 Therapeutic strategies targeting mitochondrial dynamics
5.1 Modulating the balance of mitochondrial fusion and fission
The processes of mitochondrial fusion and fission play a dual role in the development of cisplatin resistance. An imbalance in their function is considered a key mechanism underlying this resistance (32, 35, 39). On one hand, restoring cancer cell sensitivity to cisplatin can be achieved by inhibiting the expression of mitochondrial fusion proteins or promoting the expression of fission proteins. For instance, in head and neck squamous cell carcinoma (HNSCC), hypoxia-inducible factor 1α (HIF-1α) binds to the MFF and upregulates its expression. This enhanced fission process, in turn, increases the cells’ sensitivity to cisplatin. Conversely, MFF gene silencing inhibits hypoxia-induced mitochondrial fission and reduces cancer cell sensitivity to cisplatin (98). In ovarian cancer, Piceatannol enhances sensitivity to cisplatin treatment by promoting mitochondrial fission and apoptosis. This effect is achieved through the dephosphorylation of DRP1 at serine residue 637 (99). Collectively, these studies demonstrate that enhancing the expression of specific fission proteins can increase cancer cell sensitivity to cisplatin. Conversely, other evidence indicates that inhibiting the expression of certain fission proteins may also promote cisplatin sensitivity, highlighting the context-dependent nature of these mechanisms. Research demonstrates that combining the DRP1 inhibitor mdivi-1 with cisplatin significantly enhances apoptosis in cisplatin-resistant, end-stage ovarian cancer cells (100). Similarly, in metastatic breast cancer cells, inhibiting the activity of the mitochondrial fission protein DRP1 and nuclear factor erythroid 2-related factor 2 (Nrf2) restored sensitivity to cisplatin and effectively suppressed the metastatic awakening process (40). In summary, targeted regulation of mitochondrial dynamics—the balance of fusion and fission—effectively increases sensitivity to cisplatin. This strategy hinges on a deeper understanding of the mitochondrial role in apoptosis and how morphological shifts govern drug resistance. Furthermore, developing small-molecule agonists or inhibitors (e.g., mdivi-1) that target specific proteins involved in mitochondrial fusion or fission offers a precise method to modulate mitochondrial morphology. These compounds represent promising adjuvant agents that could enhance cisplatin efficacy, providing novel strategies for cancer therapy.
5.2 Targeting mitophagy
The functional synergy between mitophagy and mitochondrial dynamics collectively influences cisplatin resistance, highlighting the importance of targeting mitophagy. Research has found that upregulating ceramide synthase 6 (CerS6) expression markedly suppresses mitophagy and promotes mitochondrial fission in oral squamous cell carcinoma, thereby inducing apoptosis in resistant cells (101). Similarly, treatment with the mitochondria-targeting aggregation-induced emission molecule DP-PPh3 effectively blocks autophagic flux by preventing autophagosome degradation, thereby overcoming cisplatin resistance in non-small cell lung cancer cells (102). Similarly, in liver cancer, mitophagy inhibitors also enhance sensitivity to cisplatin and induce tumor cell apoptosis (103, 104). Collectively, these studies demonstrate that inhibiting mitophagy can enhance tumor cell sensitivity to cisplatin. Conversely, and somewhat paradoxically, promoting mitophagy can also induce apoptosis in resistant cells. Studies have revealed that mitochondria-targeted platinum(II) complexes can activate mitophagy and trigger apoptosis mediated by endoplasmic reticulum stress in cisplatin-resistant cells (105). Therefore, specifically targeting the process of mitophagy can effectively induce apoptosis in cisplatin-resistant cells. This mechanism highlights the critical role of mitophagy in regulating cell death and offers a novel therapeutic strategy to overcome cisplatin resistance.
5.3 Targeting mitochondrial metabolism and energy production
Given the significant role of the interplay between mitochondrial dynamics and cellular energy metabolism in mediating cisplatin resistance, and considering that resistant cells typically rely on OXPHOS rather than glycolysis, targeting OXPHOS or impairing metabolic flexibility have emerged as pivotal strategies to enhance cisplatin sensitivity (106, 107). In cisplatin-resistant lung cancer cells, OXPHOS activity is significantly elevated. Treatment with the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) effectively suppresses OXPHOS levels in these cells, thereby enhancing their sensitivity to cisplatin (108). In ovarian cancer cells, inhibiting their ability to switch between OXPHOS and glycolysis enhances the efficacy of platinum-based chemotherapy (109). Collectively, these findings demonstrate that suppressing OXPHOS in resistant cells enhances their sensitivity to cisplatin. Similarly, reducing ATP levels in these cells produces a comparable effect. Research indicates that metformin inhibits the p32/OPA1 axis, thereby reducing ATP synthesis and inducing mitochondrial fission. When used in combination with cisplatin, metformin significantly diminishes the viability of resistant cells (32). Therefore, targeted intervention in mitochondrial metabolism and energy production can initiate a cascade of events related to mitochondrial dynamics. These changes not only enhance mitochondrial function but also increase cellular sensitivity to cisplatin, ultimately improving the drug’s therapeutic efficacy against tumors. This interventional strategy provides a novel approach for optimizing mitochondrial function and opens new avenues for the clinical application of chemotherapeutic agents like cisplatin, showing significant potential for future cancer therapy.
5.4 Mitochondria-targeted drug delivery systems
The development of mitochondria-targeted nanoparticles through nanocarrier systems can circumvent conventional drug resistance mechanisms. Specifically, cisplatin-loaded nanoparticles (NPcis) exploit endocytic pathways for drug delivery, bypassing LRRC8A-mediated resistance and effectively eliminating resistant cells (110). Similarly, when a Pt(IV) prodrug—a type of platinum complex—is conjugated with the mitochondria-targeting ligand triphenylphosphine and specific peptide molecules, the resulting compound effectively disrupts mitochondrial metabolism. This disruption subsequently activates intrinsic apoptotic pathways, ultimately inducing cell death. This multi-level mechanism of action enhances the precision of drug targeting to diseased cells and thereby offers novel therapeutic avenues for cancer treatment (111, 112). Furthermore, in photodynamic therapy (PDT), the application of specific mitochondria-targeted photosensitizers can efficiently generate ROS upon irradiation at specific wavelengths. These ROS precisely target and damage mitochondria within tumor cells, thereby significantly disrupting cellular energy metabolism and ultimately reducing cell viability. This precisely targeted mitochondrial damage not only directly compromises tumor cell viability but also significantly potentiates the efficacy of platinum-based chemotherapy, enabling more effective tumor suppression and ultimately improving overall therapeutic outcomes (113, 114). Consequently, the innovative approach of utilizing nanoparticle delivery systems to overcome cisplatin resistance demonstrates high potential for clinical translation.
5.5 Preclinical in vivo models and clinical translation of therapeutic targeting of mitochondrial dynamics
Preclinical in vivo and clinical translational studies form a critical translational bridge, validating the therapeutic promise of targeting mitochondrial dynamics to overcome cisplatin resistance. Studies in xenograft mouse models demonstrated the critical role of mitochondrial dynamics in cisplatin resistance. In L1210/DDP leukemia models, the Drp1 inhibitor Mdivi-1 attenuated cisplatin-induced cell death, caspase-3 activation, and ROS elevation, whereas promoting mitochondrial fission reversed these effects (31). Similarly, in SKOV3/DDP ovarian cancer models, specific knockout of the fusion protein Mfn2 restored tumor sensitivity to cisplatin (38). These in vivo findings collectively elucidate the pivotal role of targeting mitochondrial dynamics proteins in reversing cisplatin resistance and underscore their therapeutic potential. Metformin is extensively utilized in clinical practice as a first-line therapy for glycemic control (115). Furthermore, numerous studies indicate its efficacy in counteracting cisplatin resistance, suggesting promise for clinical application (116, 117). In studies using A549/DDP xenograft models, metformin was found to induce mitochondrial fission and deplete ATP, thereby sensitizing the tumors to cisplatin and leading to significant tumor growth inhibition upon combination treatment (32). Phase II clinical trial results demonstrated a modest improvement in overall survival with the metformin-cisplatin combination in non-small cell lung cancer patients, and shown a favorable tolerability profile in head and neck squamous cell carcinoma (116, 118).These findings underscore the significant translational value of targeting mitochondrial dynamics in cancer therapy.
In summary, while most research on targeting mitochondrial dynamics to overcome cisplatin resistance remains preclinical, the field is rapidly evolving beyond the sole targeting of dynamics proteins to encompass closely linked processes like mitophagy and mitochondrial metabolism. Furthermore, the continuous advancement of nanocarrier technology is poised to refine these therapeutic strategies. This review consolidates current pharmacological strategies that target mitochondrial dynamics to combat cisplatin resistance (Table 2). By integrating both preclinical and clinical data, it affirms the synergistic therapeutic promise of combining cisplatin with mitochondrial dynamics-targeted agents (Table 3).
Table 2. Advances in drug development targeting mitochondrial dynamics.
Table 3. Advances in cisplatin combination with mitochondrial dynamics-targeted agents.
6 Conclusions and perspectives
Remodeling of mitochondrial dynamics has emerged as a pivotal hub in cisplatin resistance. An imbalance between fusion and fission not only promotes the formation of hyperfused networks but, conversely, excessive fission can also facilitate the development of drug resistance. This review extends beyond examining the cisplatin resistance mechanisms directly driven by imbalances in mitochondrial dynamics to incorporate their interplay with mitophagy, metabolism, and the tumor immune microenvironment, thereby synthesizing their synergistic mechanisms from a broader perspective. Furthermore, it provides a systematic discussion on therapeutic strategies, including modulating mitochondrial fusion/fission, targeting mitophagy, intervening in mitochondrial metabolism and energy supply, and developing mitochondrial-targeted drug delivery systems. By synthesizing clinically relevant data, this work underscores the significant translational value of developing drugs targeting mitochondrial dynamics. Nonetheless, numerous promising avenues for future investigation remain. For instance, developing dynamic monitoring techniques using novel fluorescent probes (e.g., DHX-Fe) to track real-time morphology-metabolism changes in live cells would help elucidate the spatiotemporal dynamics of drug resistance development (122); Future studies should focus on constructing organelle interaction networks to investigate the role of endoplasmic reticulum-mitochondria contact sites (MAMs) in cisplatin resistance development, and to examine the regulatory mechanisms of the INF2-ER-mitochondria axis (123). Undoubtedly, these research directions provide novel avenues for overcoming cisplatin resistance.
However, translating mitochondrial dynamics-targeted strategies into clinical treatments for reversing cisplatin resistance faces substantial challenges. The specific mechanisms by which mitochondrial dynamics drive resistance vary significantly across cancer types and even within individual tumors. Moreover, precisely modulating the balance between fission and fusion remains difficult. These challenges underscore the critical need to develop biomarker-based stratification strategies. Consequently, a primary objective in drug development is to learn how to selectively modulate mitochondrial function in diseased cells without affecting healthy ones.
This review integrates recent advances in mitochondrial dynamics to build a theoretical and translational framework for overcoming cisplatin resistance. Future research should focus on three key areas: dynamic monitoring, targeted delivery, and clinical validation, to establish novel tumor treatment strategies based on the precise targeting of mitochondria.
Author contributions
ZW: Formal Analysis, Writing – original draft, Funding acquisition, Visualization, Writing – review & editing, Resources. WH: Writing – original draft, Formal Analysis, Writing – review & editing, Investigation. WS: Formal Analysis, Investigation, Software, Writing – original draft. ZY: Investigation, Formal Analysis, Writing – original draft, Methodology. YL: Data curation, Investigation, Writing – original draft.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by grants from the National Natural Science Foundation of China (NSFC General Program, Grant No. 82474117 to Ziliang Wang), the Shanghai Municipal Talent Affairs Bureau (2024 Shanghai Oriental Talents Program - Top-notch Project, Grant No. BJWS2024059 to Ziliang Wang), the Shanghai Municipal Natural Science Foundation (General Program, Grant No. 24ZR1465200 to Ziliang Wang), and the Open Project of the National Key Laboratory of Immunity and Inflammation (Grant No. NKLII2024010 to Ziliang Wang).
Conflict of interest
The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Li W, Gui Y, Guo C, Huang Y, Liu Y, Yu X, et al. Molecular mechanisms of mitochondrial quality control. Trans neurodegeneration. (2025) 14:45. doi: 10.1186/s40035-025-00505-5
2. Tang Q, Liu W, Zhang Q, Huang J, Hu C, Liu Y, et al. Dynamin-related protein 1-mediated mitochondrial fission contributes to IR-783-induced apoptosis in human breast cancer cells. J Cell Mol Med. (2018) 22:4474–85. doi: 10.1111/jcmm.13749
3. Gilkerson R, Kaur H, Carrillo O, and Ramos I. OMA1-mediated mitochondrial dynamics balance organellar homeostasis upstream of cellular stress responses. Int J Mol Sci. (2024) 25:4566. doi: 10.3390/ijms25084566
4. Lei Y, Gan M, Qiu Y, Chen Q, Wang X, Liao T, et al. The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights. Cell Mol Biol letters. (2024) 29:59. doi: 10.1186/s11658-024-00572-y
5. Willett BAS, Thompson SB, Chen V, Dareshouri A, Jackson CL, Brunetti T, et al. Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells. Cell Rep. (2025) 44:115610. doi: 10.1016/j.celrep.2025.115610
6. Chen W, Zhao H, and Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal transduction targeted Ther. (2023) 8:333. doi: 10.1038/s41392-023-01547-9
7. Liu D, Fan YB, Tao XH, Pan WL, Wu YX, Wang XH, et al. Mitochondrial quality control in sarcopenia: updated overview of mechanisms and interventions. Aging disease. (2021) 12:2016–30. doi: 10.14336/AD.2021.0427
8. Zacharioudakis E and Gavathiotis E. Mitochondrial dynamics proteins as emerging drug targets. Trends Pharmacol Sci. (2023) 44:112–27. doi: 10.1016/j.tips.2022.11.004
9. Xiong PY, Potus F, Chan W, and Archer SL. Models and molecular mechanisms of world health organization group 2 to 4 pulmonary hypertension. Hypertension (Dallas Tex: 1979). (2018) 71:34–55. doi: 10.1161/HYPERTENSIONAHA.117.08824
10. García-Peña LM, Abel ED, and Pereira RO. Mitochondrial dynamics, diabetes, and cardiovascular disease. Diabetes. (2024) 73:151–61. doi: 10.2337/dbi23-0003
11. Li T, Zhu K, Tong H, Sun Y, Zhu J, Qin Z, et al. Cancer-associated fibroblast derived CXCL14 drives cisplatin chemoresistance by enhancing nucleotide excision repair in bladder cancer. J Exp Clin Cancer research: CR. (2025) 44:265. doi: 10.1186/s13046-025-03487-4
12. Hu Q, Chen Q, Yang W, Ren A, Tan J, and Huang T. GPX3 promotes cisplatin resistance in TNBC by manipulating ROS-TGFB1-ZEB2. Cell communication signaling: CCS. (2025) 23:355. doi: 10.1186/s12964-025-02356-z
13. Guan R, Li C, Jiao R, Li J, Wei R, Feng C, et al. MRPL21-PARP1 axis promotes cisplatin resistance in head and neck squamous cell carcinoma by inhibiting autophagy through the PI3K/AKT/mTOR signaling pathway. J Exp Clin Cancer research: CR. (2025) 44:221. doi: 10.1186/s13046-025-03482-9
14. Chen Y, Shi J, Wang X, Zhou L, Wang Q, Xie Y, et al. An antioxidant feedforward cycle coordinated by linker histone variant H1.2 and NRF2 that drives nonsmall cell lung cancer progression. Proc Natl Acad Sci United States America. (2023) 120:e2306288120. doi: 10.1073/pnas.2306288120
15. Phung HM, Lee S, Hwang JH, and Kang KS. Preventive effect of muscone against cisplatin nephrotoxicity in LLC-PK1 cells. Biomolecules. (2020) 10:1444. doi: 10.3390/biom10101444
16. Liu H, Tang L, Li Y, Xie W, Zhang L, Tang H, et al. Nasopharyngeal carcinoma: current views on the tumor microenvironment’s impact on drug resistance and clinical outcomes. Mol cancer. (2024) 23:20. doi: 10.1186/s12943-023-01928-2
17. Yano K, Todokoro I, Kamioka H, Tomono T, and Ogihara T. Functional alterations of multidrug resistance-associated proteins 2 and 5, and breast cancer resistance protein upon snail-induced epithelial-mesenchymal transition in HCC827 cells. Biol Pharm bulletin. (2021) 44:103–11. doi: 10.1248/bpb.b20-00693
18. Milosevic V, Kopecka J, Salaroglio IC, Libener R, Napoli F, Izzo S, et al. Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5. Int J cancer. (2020) 146:192–207. doi: 10.1002/ijc.32419
19. Li Z, Shu X, Liu X, Li Q, Hu Y, Jia B, et al. Cellular and molecular mechanisms of chemoresistance for gastric cancer. Int J Gen Med. (2024) 17:3779–88. doi: 10.2147/IJGM.S473749
20. Wang BR, Chu DX, Cheng MY, Jin Y, Luo HG, and Li N. Progress of HOTAIR-microRNA in hepatocellular carcinoma. Hereditary Cancer Clin practice. (2022) 20:4. doi: 10.1186/s13053-022-00210-8
21. Qin B, Tang D, and Zhang M. miR-149-3p targeting TMPRSS4 regulates the sensitivity to cisplatin to inhibit the progression of lung cancer. Biomolecules biomedicine. (2024) 25:165–76. doi: 10.17305/bb.2024.11163
22. Krasniqi E, Sacconi A, Marinelli D, Pizzuti L, Mazzotta M, Sergi D, et al. MicroRNA-based signatures impacting clinical course and biology of ovarian cancer: a miRNOmics study. biomark Res. (2021) 9:57. doi: 10.1186/s40364-021-00289-6
23. Šimčíková D, Gardáš D, Pelikán T, Moráň L, Hruda M, Hložková K, et al. Metabolism of primary high-grade serous ovarian carcinoma (HGSOC) cells under limited glutamine or glucose availability. Cancer Metab. (2024) 12:27. doi: 10.1186/s40170-024-00355-1
24. Mohammed WH, Sulaiman GM, Abomughaid MM, Klionsky DJ, and Abu-Alghayth MH. The dual role of autophagy in suppressing and promoting hepatocellular carcinoma. Front Cell Dev Biol. (2024) 12:1472574. doi: 10.3389/fcell.2024.1472574
25. Bondar D and Karpichev Y. Poly(ADP-ribose) polymerase (PARP) inhibitors for cancer therapy: advances, challenges, and future directions. Biomolecules. (2024) 14:1269. doi: 10.3390/biom14101269
26. Ubanako P, Mirza S, Ruff P, and Penny C. Exosome-mediated delivery of siRNA molecules in cancer therapy: triumphs and challenges. Front Mol biosciences. (2024) 11:1447953. doi: 10.3389/fmolb.2024.1447953
27. Kim MC, Hwang SH, Yang Y, Kim NY, and Kim Y. Reduction in mitochondrial oxidative stress mediates hypoxia-induced resistance to cisplatin in human transitional cell carcinoma cells. Neoplasia (New York NY). (2021) 23:653–62. doi: 10.1016/j.neo.2021.05.013
28. Girolimetti G, Guerra F, Iommarini L, Kurelac I, Vergara D, Maffia M, et al. Platinum-induced mitochondrial DNA mutations confer lower sensitivity to paclitaxel by impairing tubulin cytoskeletal organization. Hum Mol Genet. (2017) 26:2961–74. doi: 10.1093/hmg/ddx186
29. Meng J, Jin Z, Zhao P, Zhao B, Fan M, and He Q. A multistage assembly/disassembly strategy for tumor-targeted CO delivery. Sci Adv. (2020) 6:eaba1362. doi: 10.1126/sciadv.aba1362
30. Cocetta V, Ragazzi E, and Montopoli M. Mitochondrial involvement in cisplatin resistance. Int J Mol Sci. (2019) 20:3384. doi: 10.3390/ijms20143384
31. Han XJ, Shi SL, Wei YF, Jiang LP, Guo MY, Wu HL, et al. Involvement of mitochondrial dynamics in the antineoplastic activity of cisplatin in murine leukemia L1210 cells. Oncol Rep. (2017) 38:985–92. doi: 10.3892/or.2017.5765
32. Yu CX, Peng ZQ, Wang T, Qu XH, Yang P, Huang SR, et al. p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer. Acta Biochim Biophys Sinica. (2024) 56:34–43. doi: 10.3724/abbs.2023247
33. Fang HY, Chen CY, Chiou SH, Wang YT, Lin TY, Chang HW, et al. Overexpression of optic atrophy 1 protein increases cisplatin resistance via inactivation of caspase-dependent apoptosis in lung adenocarcinoma cells. Hum pathology. (2012) 43:105–14. doi: 10.1016/j.humpath.2011.04.012
34. Fan S, Liu B, Sun L, Lv XB, Lin Z, Chen W, et al. Mitochondrial fission determines cisplatin sensitivity in tongue squamous cell carcinoma through the BRCA1-miR-593-5p-MFF axis. Oncotarget. (2015) 6:14885–904. doi: 10.18632/oncotarget.3659
35. Lv GY, Mu WT, Cao YN, Sun XD, Wei F, Chai KY, et al. Cisplatin-induced disruption of mitochondrial divisome leads to enhanced cisplatin resistance in cholangiocarcinoma. J Hepatol. (2025) 83:917–930. doi: 10.1016/j.jhep.2025.03.028
36. Cribbs JT and Strack S. Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. (2007) 8:939–44. doi: 10.1038/sj.embor.7401062
37. Tábara LC, Segawa M, and Prudent J. Molecular mechanisms of mitochondrial dynamics. Nat Rev Mol Cell Biol. (2025) 26:123–46. doi: 10.1038/s41580-024-00785-1
38. Zou GP, Yu CX, Shi SL, Li QG, Wang XH, Qu XH, et al. Mitochondrial dynamics mediated by DRP1 and MFN2 contributes to cisplatin chemoresistance in human ovarian cancer SKOV3 cells. J Cancer. (2021) 12:7358–73. doi: 10.7150/jca.61379
39. Li X, Wu Q, Ma F, Zhang X, Cai L, and Yang X. Mitochondrial fission factor promotes cisplatin resistancein hepatocellular carcinoma. Acta Biochim Biophys Sinica. (2022) 54:301–10. doi: 10.3724/abbs.2022007
40. Romani P, Nirchio N, Arboit M, Barbieri V, Tosi A, Michielin F, et al. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance. Nat Cell Biol. (2022) 24:168–80. doi: 10.1038/s41556-022-00843-w
41. Burman JL, Pickles S, Wang C, Sekine S, Vargas JNS, Zhang Z, et al. Mitochondrial fission facilitates the selective mitophagy of protein aggregates. J Cell Biol. (2017) 216:3231–47. doi: 10.1083/jcb.201612106
42. Pickles S, Vigié P, and Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr biology: CB. (2018) 28:R170–r85. doi: 10.1016/j.cub.2018.01.004
43. Um JH and Yun J. Emerging role of mitophagy in human diseases and physiology. BMB Rep. (2017) 50:299–307. doi: 10.5483/BMBRep.2017.50.6.056
44. Guan Y and Yan Z. Mitochondrial quality control. Adv Exp Med Biol. (2025) 1478:51–60. doi: 10.1007/978-3-031-88361-3_3
45. Twig G and Shirihai OS. The interplay between mitochondrial dynamics and mitophagy. Antioxidants Redox Signaling. (2011) 14:1939–51. doi: 10.1089/ars.2010.3779
46. Xian H and Liou YC. Functions of outer mitochondrial membrane proteins: mediating the crosstalk between mitochondrial dynamics and mitophagy. Cell Death differentiation. (2021) 28:827–42. doi: 10.1038/s41418-020-00657-z
47. Bordi M, Nazio F, and Campello S. The close interconnection between mitochondrial dynamics and mitophagy in cancer. Front Oncol. (2017) 7:81. doi: 10.3389/fonc.2017.00081
48. Liu Y, Fu Y, Hu X, Chen S, Miao J, Wang Y, et al. Caveolin-1 knockdown increases the therapeutic sensitivity of lung cancer to cisplatin-induced apoptosis by repressing Parkin-related mitophagy and activating the ROCK1 pathway. J Cell Physiol. (2020) 235:1197–208. doi: 10.1002/jcp.29033
49. Wang J and Wu GS. Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem. (2014) 289:17163–73. doi: 10.1074/jbc.M114.558288
50. Wang Q and Liu C. Mitophagy plays a “double-edged sword” role in the radiosensitivity of cancer cells. J Cancer Res Clin Oncol. (2024) 150:14. doi: 10.1007/s00432-023-05515-2
51. Chen Y, Chen HN, Wang K, Zhang L, Huang Z, Liu J, et al. Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma. J hepatology. (2019) 70:66–77. doi: 10.1016/j.jhep.2018.09.022
52. Crean-Tate KK, Braley C, Dey G, Esakov E, Saygin C, Trestan A, et al. Pretreatment with LCK inhibitors chemosensitizes cisplatin-resistant endometrioid ovarian tumors. J Ovarian Res. (2021) 14:55. doi: 10.1186/s13048-021-00797-x
53. Zuo J, Zhang Z, Li M, Yang Y, Zheng B, Wang P, et al. The crosstalk between reactive oxygen species and noncoding RNAs: from cancer code to drug role. Mol cancer. (2022) 21:30. doi: 10.1186/s12943-021-01488-3
54. Wang Z, Tang S, Cai L, Wang Q, Pan D, Dong Y, et al. DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma. Br J cancer. (2024) 130:1744–57. doi: 10.1038/s41416-024-02670-2
55. Xie Q, Wu Q, Horbinski CM, Flavahan WA, Yang K, Zhou W, et al. Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci. (2015) 18:501–10. doi: 10.1038/nn.3960
56. Liu D, Sun Z, Ye T, Li J, Zeng B, Zhao Q, et al. The mitochondrial fission factor FIS1 promotes stemness of human lung cancer stem cells via mitophagy. FEBS Open bio. (2021) 11:1997–2007. doi: 10.1002/2211-5463.13207
57. Janiszewska M, Suvà ML, Riggi N, Houtkooper RH, Auwerx J, Clément-Schatlo V, et al. Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev. (2012) 26:1926–44. doi: 10.1101/gad.188292.112
58. Vlashi E, Lagadec C, Vergnes L, Matsutani T, Masui K, Poulou M, et al. Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci United States America. (2011) 108:16062–7. doi: 10.1073/pnas.1106704108
59. Ludikhuize MC, Meerlo M, Gallego MP, Xanthakis D, Burgaya Julià M, Nguyen NTB, et al. Mitochondria define intestinal stem cell differentiation downstream of a FOXO/notch axis. Cell Metab. (2020) 32:889–900.e7. doi: 10.1016/j.cmet.2020.10.005
60. Prieto J, León M, Ponsoda X, Sendra R, Bort R, Ferrer-Lorente R, et al. Early ERK1/2 activation promotes DRP1-dependent mitochondrial fission necessary for cell reprogramming. Nat Commun. (2016) 7:11124. doi: 10.1038/ncomms11124
61. Zhang GE, Jin HL, Lin XK, Chen C, Liu XS, Zhang Q, et al. Anti-tumor effects of Mfn2 in gastric cancer. Int J Mol Sci. (2013) 14:13005–21. doi: 10.3390/ijms140713005
62. Wang W, Xie Q, Zhou X, Yao J, Zhu X, Huang P, et al. Mitofusin-2 triggers mitochondria Ca2+ influx from the endoplasmic reticulum to induce apoptosis in hepatocellular carcinoma cells. Cancer letters. (2015) 358:47–58. doi: 10.1016/j.canlet.2014.12.025
63. Saito K, Zhang Q, Yang H, Yamatani K, Ai T, Ruvolo V, et al. Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition. Blood advances. (2021) 5:4233–55. doi: 10.1182/bloodadvances.2020003661
64. Noh S, Phorl S, Naskar R, Oeum K, Seo Y, Kim E, et al. p32/C1QBP regulates OMA1-dependent proteolytic processing of OPA1 to maintain mitochondrial connectivity related to mitochondrial dysfunction and apoptosis. Sci Rep. (2020) 10:10618. doi: 10.1038/s41598-020-67457-w
65. Saha SK, Kim KE, Islam SMR, Cho SG, and Gil M. Systematic multiomics analysis of alterations in C1QBP mRNA expression and relevance for clinical outcomes in cancers. J Clin Med. (2019) 8:513. doi: 10.3390/jcm8040513
66. Chen H, Lin C, Lu C, Wang Y, Han R, Li L, et al. Metformin-sensitized NSCLC cells to osimertinib via AMPK-dependent autophagy inhibition. Clin Respir J. (2019) 13:781–90. doi: 10.1111/crj.13091
67. Galloway CA and Yoon Y. Mitochondrial morphology in metabolic diseases. Antioxidants Redox Signaling. (2013) 19:415–30. doi: 10.1089/ars.2012.4779
68. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. (2001) 120:1183–92. doi: 10.1053/gast.2001.23256
69. Zhang Y, Jiang L, Hu W, Zheng Q, and Xiang W. Mitochondrial dysfunction during in vitro hepatocyte steatosis is reversed by omega-3 fatty acid-induced up-regulation of mitofusin 2. Metabolism: Clin experimental. (2011) 60:767–75. doi: 10.1016/j.metabol.2010.07.026
70. Guo K, Lu J, Huang Y, Wu M, Zhang L, Yu H, et al. Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling. PloS One. (2015) 10:e0125176. doi: 10.1371/journal.pone.0125176
71. Cruz-Bermúdez A, Laza-Briviesca R, Vicente-Blanco RJ, García-Grande A, Coronado MJ, Laine-Menéndez S, et al. Cisplatin resistance involves a metabolic reprogramming through ROS and PGC-1α in NSCLC which can be overcome by OXPHOS inhibition. Free Radical Biol Med. (2019) 135:167–81. doi: 10.1016/j.freeradbiomed.2019.03.009
72. Huang Y, Bell LN, Okamura J, Kim MS, Mohney RP, Guerrero-Preston R, et al. Phospho-ΔNp63α/SREBF1 protein interactions: bridging cell metabolism and cisplatin chemoresistance. Cell Cycle (Georgetown Tex). (2012) 11:3810–27. doi: 10.4161/cc.22022
73. Pervushin NV, Yapryntseva MA, Panteleev MA, Zhivotovsky B, and Kopeina GS. Cisplatin resistance and metabolism: simplification of complexity. Cancers. (2024) 16:3082. doi: 10.3390/cancers16173082
74. Wang Y, Ding Y, Wuren T, and Luo P. Reprogramming of hypoxia-induced metabolic disorder in mouse kidneys by mesenchymal stem cells through improving mitochondrial dynamics and function. J Biochem Mol toxicology. (2025) 39:e70291. doi: 10.1002/jbt.70291
75. Park SJ, Cerella C, Kang JM, Byun J, Kum D, Orlikova-Boyer B, et al. Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming. J Exp Clin Cancer research: CR. (2025) 44:114. doi: 10.1186/s13046-025-03372-0
76. Zhao QY, Liu WJ, Wang JG, Li H, Lv JL, Wang Y, et al. Increasing cisplatin exposure promotes small-cell lung cancer transformation after a shift from glucose metabolism to fatty acid metabolism. J Cancer Res Clin Oncol. (2025) 151:126. doi: 10.1007/s00432-025-06164-3
77. Li SS, Zhang B, Huang C, Fu Y, Zhao Y, Gong L, et al. FAO-fueled OXPHOS and NRF2-mediated stress resilience in MICs drive lymph node metastasis. Proc Natl Acad Sci United States America. (2025) 122:e2411241122. doi: 10.1073/pnas.2411241122
78. Wangpaichitr M, Kandemir H, Li YY, Wu C, Nguyen D, Feun LG, et al. Relationship of metabolic alterations and PD-L1 expression in cisplatin resistant lung cancer. Cell Dev Biol. (2017) 6:183. doi: 10.4172/2168-9296.1000183
79. Li X, Zhang H, Cao Z, Xiao H, Weng C, and Zheng Q. Mitochondria-targeted and ROS-sensitive main-chain ruthenium polymer overcomes cancer drug resistance. J Controlled release: Off J Controlled Release Society. (2025) 383:113840. doi: 10.1016/j.jconrel.2025.113840
80. Mirzaei S, Hushmandi K, Zabolian A, Saleki H, Torabi SMR, Ranjbar A, et al. Elucidating role of reactive oxygen species (ROS) in cisplatin chemotherapy: A focus on molecular pathways and possible therapeutic strategies. Molecules (Basel Switzerland). (2021) 26:2382. doi: 10.3390/molecules26082382
81. Marullo R, Werner E, Degtyareva N, Moore B, Altavilla G, Ramalingam SS, et al. Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PloS One. (2013) 8:e81162. doi: 10.1371/journal.pone.0081162
82. Zaidieh T, Smith JR, Ball KE, and An Q. Mitochondrial DNA abnormalities provide mechanistic insight and predict reactive oxygen species-stimulating drug efficacy. BMC cancer. (2021) 21:427. doi: 10.1186/s12885-021-08279-5
83. Shen M, Xu Z, Xu W, Jiang K, Zhang F, Ding Q, et al. Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway. J Exp Clin Cancer research: CR. (2019) 38:149. doi: 10.1186/s13046-019-1161-8
84. Serasinghe MN and Chipuk JE. Mitochondrial fission in human diseases. Handb Exp Pharmacol. (2017) 240:159–88. doi: 10.1007/164_2016_38
85. Capece D, Verzella D, Di Francesco B, Alesse E, Franzoso G, and Zazzeroni F. NF-κB and mitochondria cross paths in cancer: mitochondrial metabolism and beyond. Semin Cell Dev Biol. (2020) 98:118–28. doi: 10.1016/j.semcdb.2019.05.021
86. Cui X, Xu J, and Jia X. Targeting mitochondria: a novel approach for treating platinum-resistant ovarian cancer. J Trans Med. (2024) 22:968. doi: 10.1186/s12967-024-05770-y
87. Deng X, Xie J, Yang L, Yang DH, and Zheng S. Editorial: Tumor microenvironment, immunotherapy, and drug resistance in breast and gastrointestinal cancer. Front Immunol. (2023) 14:1265704. doi: 10.3389/fimmu.2023.1265704
88. Sun J, Zhou S, Sun Y, and Zeng Y. The clinical significance and potential therapeutic target of tumor-associated macrophage in non-small cell lung cancer. Front Med. (2025) 12:1541104. doi: 10.3389/fmed.2025.1541104
89. Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. (2011) 25:2465–79. doi: 10.1101/gad.180331.111
90. Wang B, Liu Y, Liao Z, Wu H, Zhang B, and Zhang L. EZH2 in hepatocellular carcinoma: progression, immunity, and potential targeting therapies. Exp Hematol Oncol. (2023) 12:52. doi: 10.1186/s40164-023-00405-2
91. Zhu X, Li Y, Liu H, and Xiao Z. FN1 from cancer-associated fibroblasts orchestrates pancreatic cancer metastasis via integrin-PI3K/AKT signaling. Front Oncol. (2025) 15:1595523. doi: 10.3389/fonc.2025.1595523
92. Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, et al. Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to foster an immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. (2015) 75:5034–45. doi: 10.1158/0008-5472.CAN-14-3098
93. Li Y and Li Z. Potential mechanism underlying the role of mitochondria in breast cancer drug resistance and its related treatment prospects. Front Oncol. (2021) 11:629614. doi: 10.3389/fonc.2021.629614
94. Wang Y, Ma X, Zhou W, Liu C, and Zhang H. Reregulated mitochondrial dysfunction reverses cisplatin resistance microenvironment in colorectal cancer. Smart Med. (2022) 1:e20220013. doi: 10.1002/SMMD.20220013
95. Cai J, Wang J, Huang Y, Wu H, Xia T, Xiao J, et al. ERK/Drp1-dependent mitochondrial fission is involved in the MSC-induced drug resistance of T-cell acute lymphoblastic leukemia cells. Cell Death disease. (2016) 7:e2459. doi: 10.1038/cddis.2016.370
96. Huang CY, Chiang SF, Chen WT, Ke TW, Chen TW, You YS, et al. HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer. Cell Death disease. (2018) 9:1004. doi: 10.1038/s41419-018-1019-6
97. Bao D, Zhao J, Zhou X, Yang Q, Chen Y, Zhu J, et al. Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression. Oncogene. (2019) 38:5007–20. doi: 10.1038/s41388-019-0772-z
98. Wu K, Mao YY, Chen Q, Zhang B, Zhang S, Wu HJ, et al. Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma. Cell Oncol (Dordrecht Netherlands). (2021) 44:1167–81. doi: 10.1007/s13402-021-00629-6
99. Farrand L, Byun S, Kim JY, Im-Aram A, Lee J, Lim S, et al. Piceatannol enhances cisplatin sensitivity in ovarian cancer via modulation of p53, X-linked inhibitor of apoptosis protein (XIAP), and mitochondrial fission. J Biol Chem. (2013) 288:23740–50. doi: 10.1074/jbc.M113.487686
100. Qian W, Wang J, Roginskaya V, McDermott LA, Edwards RP, Stolz DB, et al. Novel combination of mitochondrial division inhibitor 1 (mdivi-1) and platinum agents produces synergistic pro-apoptotic effect in drug resistant tumor cells. Oncotarget. (2014) 5:4180–94. doi: 10.18632/oncotarget.1944
101. Li S, Wu Y, Ding Y, Yu M, and Ai Z. CerS6 regulates cisplatin resistance in oral squamous cell carcinoma by altering mitochondrial fission and autophagy. J Cell Physiol. (2018) 233:9416–25. doi: 10.1002/jcp.26815
102. Su Y, Lin H, Tu Y, Wang MM, Zhang GD, Yang J, et al. Fighting metallodrug resistance through alteration of drug metabolism and blockage of autophagic flux by mitochondria-targeting AIEgens. Chem science. (2022) 13:1428–39. doi: 10.1039/d1sc06722b
103. Park SY, Chang I, Kim JY, Kang SW, Park SH, Singh K, et al. Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. J Biol Chem. (2004) 279:7512–20. doi: 10.1074/jbc.M307677200
104. Luo L, Sun W, Zhu W, Li S, Zhang W, Xu X, et al. BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism. Cell Death disease. (2021) 12:169. doi: 10.1038/s41419-021-03456-7
105. Wang FY, Tang XM, Wang X, Huang KB, Feng HW, Chen ZF, et al. Mitochondria-targeted platinum(II) complexes induce apoptosis-dependent autophagic cell death mediated by ER-stress in A549 cancer cells. Eur J medicinal Chem. (2018) 155:639–50. doi: 10.1016/j.ejmech.2018.06.018
106. Sriramkumar S, Sood R, Huntington TD, Ghobashi AH, Vuong TT, Metcalfe TX, et al. Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer. J Trans Med. (2022) 20:246. doi: 10.1186/s12967-022-03447-y
107. Tong T, Zhai PS, Qin X, Zhang Z, Li CW, Guo HY, et al. Nuclear TOP1MT confers cisplatin resistance via pseudogene in HNSCC. J Dental Res. (2024) 103:1238–48. doi: 10.1177/00220345241272017
108. Yang T, Ng WH, Chen H, Chomchopbun K, Huynh TH, Go ML, et al. Mitochondrial-targeting MET kinase inhibitor kills erlotinib-resistant lung cancer cells. ACS medicinal Chem letters. (2016) 7:807–12. doi: 10.1021/acsmedchemlett.6b00223
109. Rickard BP, Overchuk M, Obaid G, Ruhi MK, Demirci U, Fenton SE, et al. Photochemical targeting of mitochondria to overcome chemoresistance in ovarian cancer (†). Photochem photobiology. (2023) 99:448–68. doi: 10.1111/php.13723
110. Siemer S, Bauer TA, Scholz P, Breder C, Fenaroli F, Harms G, et al. Targeting cancer chemotherapy resistance by precision medicine-driven nanoparticle-formulated cisplatin. ACS nano. (2021) 15:18541–56. doi: 10.1021/acsnano.1c08632
111. Gibson D. Platinum(iv) anticancer prodrugs - hypotheses and facts. Dalton Trans (Cambridge England: 2003). (2016) 45:12983–91. doi: 10.1039/c6dt01414c
112. Deng Z, Wang N, Liu Y, Xu Z, Wang Z, Lau TC, et al. A photocaged, water-oxidizing, and nucleolus-targeted pt(IV) complex with a distinct anticancer mechanism. J Am Chem Society. (2020) 142:7803–12. doi: 10.1021/jacs.0c00221
113. Zeng LZ, Li XL, Deng YA, Zhao RY, Song R, Yan YF, et al. Dinuclear dicationic iridium complexes for highly synergistic photodynamic and photothermal therapy to chemoresistant cancer. Inorganic Chem. (2025) 64:967–77. doi: 10.1021/acs.inorgchem.4c04282
114. Ren XX, Li XL, Zhao RY, Li Y, Song R, Han MC, et al. Dinuclear ru(II) complexes for synergetic photodynamic, photothermal, and sonodynamic therapy against cisplatin-resistant cancer. Inorganic Chem. (2025) 64:9596–607. doi: 10.1021/acs.inorgchem.5c00558
115. Wei XL, Tao MH, Li RH, Ge SH, and Xiao W. Metformin and adipose tissue: A multifaceted regulator in metabolism, inflammation, and regeneration. Endocrinol Metab (Seoul Korea). (2025) 40:523–38. doi: 10.3803/EnM.2025.2371
116. Kemnade JO, Florez M, Sabichi A, Zhang J, Jhaveri P, Chen G, et al. Phase I/II trial of metformin as a chemo-radiosensitizer in a head and neck cancer patient population. Oral Oncol. (2023) 145:106536. doi: 10.1016/j.oraloncology.2023.106536
117. Tseng SC, Huang YC, Chen HJ, Chiu HC, Huang YJ, Wo TY, et al. Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel. Biochem Pharmacol. (2013) 85:583–94. doi: 10.1016/j.bcp.2012.12.001
118. Jang SK, Hong SE, Lee DH, Kim JY, Kim JY, Hong J, et al. Inhibition of AKT enhances the sensitivity of NSCLC cells to metformin. Anticancer Res. (2021) 41:3481–7. doi: 10.21873/anticanres.15135
119. Woo SM, Min KJ, and Kwon TK. Inhibition of Drp1 Sensitizes Cancer Cells to Cisplatin-Induced Apoptosis through Transcriptional Inhibition of c-FLIP Expression. Molecules (Basel Switzerland). (2020) 25:5793. doi: 10.3390/molecules25245793
120. Xiong L, Tang Y, Liu Z, Dai J, and Wang X. BCL-2 inhibition impairs mitochondrial function and targets oral tongue squamous cell carcinoma. SpringerPlus. (2016) 5:1626. doi: 10.1186/s40064-016-3310-2
121. Salama OA, Moawed FS, Moustafa EM, and Kandil EI. Attenuation of N-nitrosodiethylamine -induced hepatocellular carcinoma by piceatannol and/or cisplatin: the interplay between nuclear factor (Erythroid derived 2)-like 2 and redox status. Asian Pacific J Cancer prevention: APJCP. (2022) 23:3895–903. doi: 10.31557/APJCP.2022.23.11.3895
122. Rizzuti S, Rosa E, Di Gregorio E, Hasallari F, Palagi L, Gallo E, et al. Multicomponent peptide and iron(III)-based hydrogel scaffolds: Enhanced MRI detection for biomedical applications. Int J pharmaceutics. (2025) 679:125749. doi: 10.1016/j.ijpharm.2025.125749
Keywords: cisplatin resistance, metabolic reprogramming, mitochondrial dynamics, mitophagy, targeted therapy, immune microenvironment
Citation: Huang W, Sun W, Yang Z, Li Y and Wang Z (2026) Mitochondrial dynamics in cisplatin resistance: molecular mechanisms and therapeutic targeting. Front. Oncol. 15:1736487. doi: 10.3389/fonc.2025.1736487
Received: 31 October 2025; Accepted: 15 December 2025; Revised: 28 November 2025;
Published: 07 January 2026.
Edited by:
Bela Ozsvari, Lunellabiotech Inc., CanadaReviewed by:
Jyoti Bala Kaushal, University of Nebraska Medical Center, United StatesDemiana H. Hanna, Cairo University, Egypt
Copyright © 2026 Huang, Sun, Yang, Li and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ziliang Wang, d2FuZ3ppbGlhbmdAc2h1dGNtLmVkdS5jbg==
†These authors have contributed equally to this work