High matrix stiffness triggers the YAP-OPA1-TET1/3 loop to drive chemoresistance via enhanced nuclear-mitochondrial communication.

Chemoresistance remains a major obstacle in prostate cancer therapy. This study demonstrates that high extracellular matrix stiffness promotes chemoresistance by disrupting mitochondrial-nuclear communication. Culturing prostate cancer cells on polyacrylamide hydrogels of varying stiffness revealed that a high-stiffness environment promotes mitochondrial fusion and enhances function. Mechanistic investigations revealed that high matrix stiffness activates YAP, leading to dysregulation of the Hippo signaling pathway, which subsequently upregulates the expression of OPA1 and induces mitochondrial fusion. This fusion triggers a reprogramming of glutamine metabolism. The resulting metabolite, α-ketoglutarate, activated DNA demethylases TET1 and TET3, causing epigenetic modifications of YAP target genes and further exacerbating Hippo pathway dysregulation. Together, this establishes a YAP-OPA1-TET1/3-mediated positive feedback loop between the nucleus and mitochondria that drives drug resistance. Crucially, targeting OPA1 disrupted this loop and reversed stiffness-induced chemoresistance. These findings reveal a novel mitochondrial-nuclear communication, offering new insights for overcoming chemoresistance in prostate cancer.