Abstract Background and Aim: Ovarian clear cell carcinomaOCCC is a metabolically distinct and chemo-resistant subtype of ovarian cancer characterized by poor prognosis and high recurrence rates. OCCC exhibits unique metabolic adaptations that enables survival under nutrient deprivation and oxidative stresses. Mitochondrial integrity is central to this adaptive capacity, yet the molecular mechanisms that preserve mitochondrial homeostasis in OCCC remain poorly defined. Recent evidence has identified the RNA-binding protein MEX3A as an oncogenic regulator in several cancers, including OCCC, where it promotes tumor progression. However, its role in regulating mitochondrial metabolism and stress adaptation is largely unexplored. This study aims to elucidate whether and how MEX3A sustains mitochondrial homeostasis to drive OCCC progression, focusing on its impact on tumor growth, mitochondrial structure and transcriptional responses to metabolic and mitochondrial stress. Methods: Endogenous MEX3A protein levels were evaluated across an OCCC cell panel by western blotting. Stable MEX3A knockdown and control cells were generated using a lentivirus shRNA system. Functional studies were performed using OCCC cell lines TOV21G,JHOC5 and in vivo orthotopic intrabursa and intrasplenic xenograft models to assess tumor growth and liver colonization. Mitochondrial function was analyzed by Seahorse metabolic flux assays, ATP quantification and NAD+/NADH measurements. Morphological and ultrastructural alterations were examined by confocal and transmission electron microscopy. Mitochondrial biogenesis genes and mitophagy markers were assessed by qPCR and immunoblotting. Results: MEX3A expression was significantly elevated in OCCC tissues and correlated with poor overall survival. Knockdown of MEX3A in OCCC cells markedly reduced primary tumor growth and significantly reduced the number of liver metastatic nodules in mouse models, demonstrating its functional importance for metastatic colonization. At the cellular level, MEX3A depletion led to loss of mitochondrial cristae integrity, fragmented morphology, reduced oxygen consumption and decreased ATP generation, indicating a dysfunctional in oxidative phosphorylation. Under mitochondrial stress induced by FCCP or liver-extract, control cells activated transcriptional programs for mitochondrial biogenesis, upregulating PGC1A, NRF2 and TFAM. In contrast, MEX3A-deficient cells failed to induce this adaptive response, leading to TOM20 degradation and defective mitochondrial recovery. Conclusion: Our study reveals MEX3A as a crucial RNA-binding protein that preserves mitochondrial integrity and enables metabolic adaptation in OCCC. By sustaining mitochondrial biogenesis and recovery following stress, MEX3A enhances OCCC fitness, tumor growth and liver colorization Citation Format: Priyanka Vinothkumar, Pei-Yi Lin, Li-Tzu Cheng, Chen-Hsin Albert Yu, Pang-Hung Hsu, Yu-Chi Chou, Wendy W. Hwang-Verslues. MEX3A sustains mitochondrial integrity and metabolic resilience to drive ovarian clear cell carcinoma progression and liver colonization abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2032.
Vinothkumar et al. (Fri,) studied this question.