High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts.

High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.