UBR5-KDM5A axis rewires redox metabolism to confer cisplatin resistance in triple-negative breast cancer via the cAMP-PKA-SIRT3 cascade.

Triple-negative breast cancer (TNBC) lacks actionable therapeutic targets and remains highly dependent on cytotoxic chemotherapy, yet the rapid emergence of cisplatin resistance severely limits clinical benefits. The molecular mechanisms underlying this resistance and effective combination strategies remain incompletely defined. Here, we identify an epigenetic-metabolic signaling axis that drives cisplatin resistance in TNBC. Mechanistically, the histone demethylase KDM5A suppresses the endogenous protein kinase A inhibitor PKIA, thereby activating the cAMP-PKA pathway, enhancing CREB phosphorylation, and upregulating mitochondrial deacetylase SIRT3 transcription. Elevated SIRT3 subsequently deacetylates and activates SOD2, reducing intracellular reactive oxygen species (ROS) levels and attenuating cisplatin-induced oxidative damage and apoptosis, thereby promoting a drug-resistant phenotype. Upstream, we demonstrate that the E3 ubiquitin ligase UBR5 directly interacts with KDM5A and mediates its ubiquitin-dependent degradation, acting as a negative regulator of this pathway. Loss or attenuation of UBR5 stabilizes KDM5A and amplifies the KDM5A-cAMP-PKA-SIRT3 signaling cascade, conferring resistance to cisplatin. Therapeutically, pharmacologic inhibition of KDM5A restores cisplatin sensitivity and suppresses tumor growth in both cellular and in vivo models. Collectively, our findings establish the UBR5-KDM5A-cAMP-PKA-SIRT3 axis as a central regulator of cisplatin resistance in TNBC and highlight KDM5A as a promising therapeutic target for combination treatment strategies.