The RAS/RAF/MEK/ERK pathway represents a highly conserved signaling cascade that plays a pivotal role in the survival and development of tumor cells. OC cisplatin resistance is regulated between p53 and RAS signaling networks through RAS/MAPK pathway activation, which mediates apoptosis and autophagy (15). Synuclein is a small neuron protein, and some studies have found that γ-synuclein is significantly upregulated in OC (16). Pan et al. (17) demonstrated that the overexpression of γ-synuclein activated ERK and downregulated JNK, collectively preventing apoptosis. This cell apoptosis is inhibited by 2–3 times, resulting in resistance to paclitaxel and Vincristine chemotherapy. However, the use of MEK1/2 inhibitors has been demonstrated to partially mitigate this resistance to paclitaxel.

Evidence indicates that high-frequency mutations in RAS/RAF result in aberrant RAS/RAF/MEK/ERK signaling activation, leading to platinum-based chemotherapy resistance in OC cells. Manning-Geist et al. found that in type I OC, 60% of LGSOC have alterations in the MAPK pathway (18), with 30–50% and 15–40% carrying RAS and RAF mutations, respectively (19). Additionally, 88% of junctional tumors (20) and 75% of mucinous ovarian tumors also have RAS or RAF mutations (21). Type II tumors almost universally have p53 mutations, and nearly half have BRCA1/BRCA2 mutations (22). Approximately 12% of HGSOC tumors, the most common histological subtype of OC, have been found to have RAS mutations. In OC, particularly in HGSOC, the percentage of RAS gene mutations is generally lower than 10%. However, the transcription of RAF and ERK1/2 can still activate the RAS/RAF/MEK/ERK pathway, which is closely related to the prognosis of OC (23). Consequently, targeting the ERK signaling pathway with RAF, MEK, and ERK inhibitors in OC patients (particularly those with LGSOC) has yielded promising preliminary clinical outcomes compared to the established standard of care (24–27) ( Table 1 ).

The JNK and p38 MAPK pathways are primarily activated by environmental and genotoxic stressors and regulate cellular responses to various stimuli, including cytokines, inflammatory factors, and growth factors. Consequently, they are often called Stress-Activated Protein Kinases, and they are primarily involved in cellular stress and apoptosis (28).

Apoptosis, a natural process of programmed cell death, is essential for regulating cellular homeostasis. Dysregulation of apoptosis is a key factor in tumorigenesis and cancer progression. Chemotherapeutic agents exert their anti-tumor effects mainly by inducing apoptosis in cancer cells. The JNK/p38 MAPK signaling pathway modulates the expression and activity of key apoptotic regulators, including the Bcl-2 family, caspase family, and p53, thereby orchestrating critical decisions in apoptotic machinery (37).

Autophagy is a cellular process of self-degradation and self-protection. Under stress conditions such as chemotherapy, hypoxia, and radiation, autophagosomes are formed to encapsulate damaged organelles and misfolded proteins in the cytoplasm and transport them to lysosomes for degradation, thereby maintaining cellular homeostasis (55). Therefore, autophagy is activated when OC cells are stimulated by chemotherapy drugs (56). Autophagosome formation and increased autophagy flux enable tumor cells to clear the cell damage caused by chemotherapy drugs so that these cells can survive under drug pressure, leading to the generation of drug resistance (57). However, excessive or sustained autophagy can directly mediate or contribute to cell death and reverse OC resistance (57, 58).

When cells are exposed to commonly used chemotherapy drugs such as cisplatin or paclitaxel, JNK/p38 MAPK activates and regulates the expression of autophagy-associated proteins, promoting autophagosome formation and enhancing autophagy flow. Beclin 1 and Microtubule-associated protein 1 light chain 3 (LC3) are crucial in autophagy. The JNK/p38 MAPK signaling pathway induces autophagy in OC cells and increases autophagosome formation and autophagic flux by promoting the conversion of LC3-I to LC3-II and the formation of autophagosomes (59). Zhu (60) et al. analyzed the mutation profiles of 62 HGSOC and found that overexpression of FGF19 in the fibroblast growth factor family promotes the phosphorylation of p38 to induce autophagy, upregulates the expression of LC3 and Beclin-1, and promotes cisplatin resistance in OC cells. Conversely, the knockdown of FGF19 downregulates the phosphorylation of p38 to reverse cisplatin chemoresistance.

The Unfolded Protein Response (UPR) is a pro-survival mechanism that is activated when unfolded or misfolded proteins accumulate in the endoplasmic reticulum (ER), leading to JNK/Ap-1 activation and increased autophagy (61). Yang et al. (62) found that JNK3 activation through the UPR pathway promoted acid/lysosomal compartment accumulation, blocked autophagy flux during ER stress, and reduced ROS levels in OC-resistant cells to promote OC cell survival.

Sustained activation of the JNK/p38 MAPK pathway can lead to apoptosis or excessive autophagy, resulting in a state of “autophagy cell death” or “autophagy addiction.” JNK/p38 MAPK can also reverse OC resistance by regulating the balance between apoptosis and autophagy (63). Zhao et al. (64) found that propranolol can upregulate the expression of LC3-II and caspase-3 by activating the ROS/JNK signaling pathway, induce apoptosis and autophagy of OC cells, and restore cell sensitivity to chemotherapy. Guo et al. (65) demonstrated that MAP2K6-FP, a genetically engineered fusion protein targeting the MAPK kinase pathway, enhances paclitaxel sensitivity in OC by inducing autophagy. This chimeric protein contains three functional domains (1): a HO8910 OC cell-specific binding peptide (2), the TAT protein transduction domain for cellular internalization, and (3) the MKK6(E) effector domain with anti-tumor activity. Mechanistically, MAP2K6-FP upregulated p38 expression, elevated LC-3 and Beclin-1/Bcl-2 levels, and amplified autophagic flux, thereby overcoming chemoresistance in OC models. Mishra et al. (66) showed that photothermal therapy can induce autophagy to overcome drug resistance by activating JNK signaling and UPR signaling pathways in OC chemoresistant cells.

While autophagy serves as a self-protection mechanism that enables resistance of OC cells to chemotherapy, sustained activation of autophagy by JNK/p38 MAPK signaling can trigger the “autophagic cell death process.” Autophagic cell death can override cellular survival mechanisms by excessive autophagy or modulating the balance between apoptosis and autophagy. This process re-sensitizes OC cells to chemotherapeutic agents and reverses OC drug resistance.

Platinum chemotherapeutic agents, such as cisplatin and carboplatin, impede DNA replication and transcription by twisting the DNA Double helix, causing single-strand breaks, double-strand breaks (DSB), and chromosome rearrangements, ultimately resulting in cell death. When DNA damage occurs, abnormal activation of the DNA damage response (DDR) is responsible for pausing the cell cycle and initiating DNA repair. Cell cycle checkpoints regulate cell cycle transitions by acting on the cell’s G1, S, and G2/M phases. This process can provide time for DNA repair when cell cycle arrest occurs, leading to chemotherapy resistance (67). However, in some cases, inducing cell cycle arrest at specific stages and increasing the accumulation of DNA damage can promote apoptosis and reverse chemoresistance in OC cells.

TME consists of immune cells, Cancer-associated Fibroblasts (CAFs), Vascular Endothelial Growth Factor (VEGF), adipocytes, Extracellular Matrix (ECM), and extracellular vesicles (EVs), which play a crucial role in OC treatment resistance. Due to the unique characteristics of OC metastasis in the peritoneal cavity, OC cells can survive in ascites as floating unicellular or multicellular spheres, forming a characteristic OC TME (87). Increasing evidence suggests that targeting the TME may be a promising strategy for reversing OC chemoresistance.

Tumor-associated macrophages, an essential component of immune cells in TME, can secrete many pro-inflammatory cytokines, TNF-α, TGF-β, IL-1, IL-6, and IL-12, to enhance the immune response. JNK can be activated by TGF-β, interferon-γ, and other mediated immune evasion mechanisms that affect OC resistance (76, 88). Mitra et al. (89) found that TGFβ1 can induce stemness and chemoresistance in OC cells by activating ERK1/2 and JNK/p38 MAPK pathways and targeting them to participate in epithelial-mesenchymal transition (EMT). Bioinformatic analysis of Gene Expression Omnibus and The Cancer Genome Atlas databases revealed that CAFs affect OC chemoresistance through the p53, cell cycle, PI3K-AKT, and MAPK pathways (90). Izar et al. (91) found that stimulating the expression of CAFs stimulated the formation of OC-specific TME, which increased HGSOC aggressiveness and drug resistance. IL-6 secreted by CAFs is one of the essential pro-inflammatory cytokines and plays a crucial role in OC resistance (92). Alspach et al. (93) reported that p38 promotes IL-6 expression by affecting the RNA-binding protein AUF1, but inhibition of p38 blocks the tumor-promoting ability of CAFs. Curtis et al. (94) found that p38 can provide nutrients through glycogen phosphorylation to alter the metabolic state in OC TEM and support the survival of drug-resistant OC cells. Samuel et al. (95) found that administering chemotherapeutic agents to OC cells induced EV release via JNK/p38 MAPK signaling, increasing drug resistance in OC cells. Octreotide, a somatostatin analogue, in combination with paclitaxel, can reverse paclitaxel resistance by inhibiting p38 and decreasing the expression of VEGF (96).

ROS, a critical regulator of TME, is closely related to the occurrence of OC resistance (97). Elevated levels of ROS can induce oxidative DNA damage and stimulate long-term activation of JNK, which plays an essential role in reversing drug resistance (98). ROS can mitigate OC resistance by oxidizing cysteine residues of ASK1, thereby activating the downstream JNK/p38 MAPK pathway (99). Li et al. (100) found that BH3-only protein mimic ABT-737 enhanced the activation of JNK and ASK1 by increasing ROS levels in cells in a time-dependent manner, overcoming cisplatin resistance in A2780/DDP cells. Ovendazole can inhibit the proliferation of drug-resistant OC cells through ROS-mediated activation of the JNK/p38 MAPK signaling pathways, leading to G1/S or G2/M cell cycle arrest (99).

Thus, JNK/p38 MAPK activation interacts with immune cells and pro-inflammatory factors in the TME to support the survival of OC cells, leading to chemoresistance. However, during persistently elevated levels of ROS, sustained activation of JNK/p38 MAPK can lead to apoptosis of otherwise drug-resistant cells. This finding offers insights into the development of novel therapeutic strategies for treating OC resistance.

Multidrug Resistance (MDR) leads to a lack of sensitivity to multiple chemotherapy drugs, which is the main reason for chemotherapy failure. The overexpression of ATP-binding cassette (ABC) transporters is the leading cause of MDR in chemotherapy. P-glycoprotein (P-gp), the most studied protein of the ABC transporter family, is encoded by the ABCB1 gene encodes and affects the uptake of chemotherapy drugs by pumping them out of tumor cells (101).

Evidence suggests that the p38 signaling pathway can enhance drug efflux and participate in OC resistance formation by inducing the upregulation of ABC transporter protein expression. p38 can increase the expression of ABC transporter proteins by activating the downstream transcription factor NF-κB, which binds to and upregulates the ABCB1 promoter. Afatinib, an ATP-competitive aniline-quinazoline compound, can inhibit ABCB1 transcriptional expression by downregulating p38-dependent activation of NF-κB, thereby reversing ABCB1-mediated MDR (102). Dual specificity phosphatase 1 (DUSP1), also known as MKP-1, is a class of phosphokinase capable of dephosphorylating MAPK substrates. Overexpression of DUSP1 leads to increased phosphorylation of p38. Kang et al. (103) found that activation of p38 by DUSP1 enhanced the expression of P-gp, but did not alter the activation of ERK1/2 and JNK1/2, ultimately affecting the efflux of anticancer drugs from the OC.

MicroRNA (miRNA) is a class of small non-coding RNAs, which are 18–25 nucleotides long, and alter tumor sensitivity to treatment by regulating gene expression and apoptosis (104). Dysregulation of miRNA expression is an important cause of OC chemotherapy resistance (105). Therefore, correcting miRNA dysregulation is a promising therapeutic strategy to reverse chemoresistance (106).

Inhibition of the JNK/p38 MAPK signaling pathway was found to downregulate the expression levels of miRNAs involved in regulating chemotherapeutic drug sensitivity-related miRNAs and mediated OC chemoresistance. Kumar et al. (107) showed that the downregulation of miR-20b targets genes such as DUSP8 and inhibits p38 in A2780/CP70 drug-resistant OC cell lines, leading to cisplatin resistance. Yin et al. (108) showed that downregulating miR-545-3p leads to cisplatin resistance by reducing the activity of the JNK signaling pathway. Fos-related antigen-1 (Fra-1), a part of the AP-1 transcription factor complex, can amplify ERK/JNK signaling and reduce chemosensitivity in OC cells by promoting miR-134 expression (109). Activation of JNK-1/c-Jun pathway was found to upregulate its miR-21 expression, leading to decreased levels of the tumor suppressor gene programmed cell death protein 4 (PDCD4), increased cell proliferation, and development of OC cisplatin resistance (110). Jiang et al. (111) showed that restoring the expression of miR-139-5p in drug-resistant cells can inhibit the expression of c-Jun, increase the expression of Bcl-xl, activate caspase-9 and caspase-3, and reverse cisplatin resistance in OC ( Table 3 ).

Further study of the JNK/p38 MAPK pathway has revealed that different activation times may lead to different cellular responses and biological effects. The JNK/p38 MAPK pathway is usually activated during the initial phase of chemotherapy to induce apoptosis or other cell death mechanisms. However, in drug-resistant cells, activation of the pathway may be delayed, attenuated, or shortened in duration.

Different activation timings may determine the fate of OC cells. Transient JNK/p38 MAPK activation is usually associated with pro-survival effects, whereas sustained JNK/p38 MAPK activation may be pro-apoptotic (112). Davis et al. (112) found that the activation time of JNK/p38 MAPK persisted for 12 hours in cisplatin-sensitive cells, while it was limited to 1–3 hours in cisplatin-resistant cells. LB100 can eliminate cisplatin-induced cell cycle arrest and sensitize OC cells to cisplatin by altering the temporal order and persistence of JNK activation (91). Elevated expression of HB-EGF (an EGFR ligand) contributes to cancer cell resistance to paclitaxel, and shedding the extracellular domain of HB-EGF can induce sustained activation of JNK/p38 MAPK to overcome this resistance (113). Mansouri et al. (114) showed that the JNK/p38 MAPK pathway plays a central role in cisplatin-induced apoptosis of OC cells by activating the expression of the downstream target pro-apoptotic cytokine FasL. Furthermore, the duration of sustained activation is a critical early determinant of cisplatin-induced apoptosis, as transient activation fails to maintain c-Jun and ATF-2 phosphorylation and upregulate FasL expression.

Thus, successful treatment depends not only on the combination and dosage of drugs but also on the timing, duration, and order of administration (115). A better understanding of the dynamic process of OC resistance will facilitate the clinical development of more effective therapeutic strategies for OC resistance.

The mechanism of drug resistance in OC is complex and multifactorial, involving multiple pathways. The PI3K/AKT pathway engages in bidirectional crosstalk with JNK/p38 MAPK, creating a dynamic equilibrium that dictates OC cell survival under therapeutic stress. Mechanistically, AKT suppresses JNK-mediated apoptosis by phosphorylating and inactivating ASK1, a key upstream kinase in the JNK pathway (116). Conversely, p38 inhibition prevents AKT dephosphorylation and inhibits the AKT pathway, thereby reinforcing PI3K/AKT-dependent survival signaling—a paradoxical interaction that underscores the complexity of pathway interdependencies (117). This stress-adaptation mechanism contributes to the development of OC resistance. For example, the ER protein HERPUD1 activates both PI3K/AKT/mTOR and p38 pathways to maintain autophagy and block apoptosis, thereby driving platinum resistance in OC models (118). Clinically, compensatory pathway activation poses a significant challenge. Resistance to PI3K/AKT inhibitors in OC patients is frequently associated with ERK upregulation and p38 suppression, suggesting a survival mechanism where ERK compensates for inhibited AKT. Notably, dual inhibition of ERK and AKT disrupts this cytoprotective feedback, synergistically eliminating cisplatin-resistant OC cells (119, 120). Growth factor signaling further amplifies this network, with FGF2 overexpression activating p38 and AKT to upregulate anti-apoptotic proteins (Bcl-2/Bcl-xL) and cell cycle drivers (Cyclin D1). Co-targeting FGF2-activated p38 and PI3K/AKT pathways reverses adriamycin resistance, highlighting the therapeutic potential of combinatorial approaches (121).

NF-κB acts as a key sink node to promote inflammatory responses and cellular survival under stress by blocking DNA damage-induced apoptosis through the inhibition of sustained activation of JNK (122, 123). Meanwhile, p38 upregulates anti-apoptotic proteins (such as Bcl-xL) and inflammatory factors (such as IL-6) through NF-κB activation. Hence, p38 promotes OC cell survival (124, 125).

Additionally, Wnt/β-catenin and HIF-1α pathways are involved in JNK/p38MAPK pathway crosstalk. Phosphorylation of β-catenin by JNK contributes to OC chemotherapy resistance by promoting cancer stem cell survival and inducing EMT (126–128). Furthermore, glycolysis mediated by the p38-HIF1α axis promotes the survival of chemoresistant OC cells in a hypoxic environment. Modulating HIF-1α activity by inhibiting p38, in combination with glucose analogues and platinum compounds, could enhance the efficacy of chemotherapy and represents a promising therapeutic strategy for OC (129).

In summary, the intricate crosstalk between JNK/p38 MAPK, PI3K/AKT, NF-κB, Wnt/β-catenin, and metabolic pathways forms a robust network that sustains OC cell survival under therapeutic stress. While this complexity poses significant challenges, it also offers multiple therapeutic vulnerabilities. Future research should focus on combinatorial therapies: Simultaneously targeting multiple nodes (e.g., PI3K/AKT + JNK/p38 + NF-κB) to overcome compensatory pathway activation.

SP600125 is a JNK inhibitor that inhibits JNK kinase activity and the JNK signaling pathway by specifically blocking the ATP-binding site of the JNK protein. There is growing evidence that SP600125 can mediate autophagy and apoptosis to overcome drug resistance in several malignant tumors and reverse OC resistance by regulating the cell cycle in the G2/M phase (122). Seino et al. (76) showed that combining cisplatin and SP600125 enhanced DNA damage to reverse cisplatin resistance, but the therapeutic effect was diminished when SP600125 was combined with paclitaxel. Notably, pretreating OC cells with SP600125 for three days before administrating cisplatin or paclitaxel inhibited basal JNK activity and reduced chemotherapy resistance without increasing toxicity. Thus, this time-staggered inhibition of JNK effectively enhances the sensitivity of cisplatin and paclitaxel. However, the clinical application of SP600125 is limited because it is a broad-spectrum JNK reversible inhibitor that is non-specific and can inhibit multiple kinases. AS602801 is an oral, selective JNK inhibitor and anticancer stem cell candidate, which has been shown to reduce the expression of survivin, making OC-resistant cells sensitive to paclitaxel but not carboplatin or cisplatin (123). In the future, AS602801 can be combined with other inhibitors to inhibit the growth and survival of OC cells more effectively.

Evidence suggests that p38 inhibitors can increase the sensitivity of OC cells to cisplatin and reverse drug resistance. SB203580, a widely used p38 inhibitor, showed a synergistic effect of cisplatin and SB203580 in OC Cisplatin IGROV-1/Pt1 cells, resulting in greater apoptosis than cisplatin alone (130). Xie et al. (131) found that metformin combined with SB203580 application inhibited Excision Repair Cross-Complementation Group 1 (ERCC1) expression in OC-resistant cells and enhanced the sensitivity of OC cisplatin-resistant cells. Additionally, JNK inhibitors can be used in combination with p38 inhibitors. Zhu et al. (132) found that SB203580 or SP600125 inhibited EMT and reduced metastasis in OC cells. Chen et al. (133) showed that SB202190 combined with SP600125 inhibited autophagy flux and EMT to inhibit drug resistance. Despite the promising evidence from in vivo and in vitro studies demonstrating the effectiveness of JNK/p38 MAPK inhibitors, progress has been slow in clinical trials. The p38 inhibitor BIRB 796 has been shown to inhibit ABCB1-mediated MDR147 and is currently undergoing clinical trials (NCT02211157) (134).

Research on JNK/p38 MAPK inhibitors in OC is still in the initial stage. JNK/p38 MAPK inhibitors may cause side effects on normal cells, affecting their efficacy and safety in vivo. Additionally, many inhibitors lack specificity and may interact by targeting other kinases, affecting drug selectivity and side effects. Furthermore, effective drug delivery remains a crucial challenge because different isoforms have different functions in a cellular environment-dependent manner. Further in-depth studies on its mechanism of action and clinical application are needed to develop new strategies and methods for treating OC.

Natural compounds derived from medicinal plants and traditional formulations have emerged as promising agents to overcome chemoresistance in OC by modulating JNK/p38 MAPK signaling. Compared with traditional chemotherapy, these compounds exhibit multi-target effects, including apoptosis induction, DNA repair suppression, and cell cycle arrest, while demonstrating lower systemic toxicity than conventional chemotherapy (135) ( Table 5 ).