TRPM7 drives PDK4-dependent MAM formation to promote chondrocyte senescence via cGAS-STING in osteoarthritis

Osteoarthritis (OA) is characterized by age-related chondrocyte senescence and cartilage degeneration, yet the underlying molecular drivers remain poorly defined. Transient receptor potential melastatin 7 (TRPM7) is a Ca 2+ ‑permeable ion channel involved in oxidative stress and cellular senescence, but its function in OA pathogenesis has not been elucidated. This study aimed to investigate the role of TRPM7 in chondrocyte senescence and OA pathogenesis and to elucidate the underlying molecular mechanisms. TRPM7 expression was examined in cartilage tissues from OA patients, aged mice, and destabilization of the medial meniscus (DMM)‑induced OA models, as well as in replicative and H 2 O 2 ‑induced senescent chondrocytes. Chondrocyte‑specific Trpm7 knockout mice, the TRPM7 channel blocker 2‑APB, and CRISPR‑Cas9‑mediated gene depletion were used to assess functional roles. Mitochondria‑associated endoplasmic reticulum membranes (MAMs) were analyzed by transmission electron microscopy. Mitochondrial Ca 2+ and reactive oxygen species (ROS) were measured with fluorescent probes. RNA sequencing and immunoprecipitation were performed to identify downstream effectors and protein interactions. The cGAS‑STING pathway was evaluated by immunoblotting, cGAMP assays, and pharmacological inhibition. OA severity was assessed by histology and micro-computed tomography. TRPM7 expression was significantly upregulated in senescent chondrocytes from OA patients, aged mice, and DMM‑induced OA models. TRPM7 inhibition or depletion suppressed chondrocyte senescence, attenuated cartilage degeneration, and reduced subchondral bone sclerosis in OA mouse models. These findings suggest that TRPM7 mediates chondrocyte senescence. Mechanistically, TRPM7 promoted MAM formation in a Ca 2+ ‑dependent manner, leading to mitochondrial Ca 2+ overload and ROS accumulation. Transcriptomic analysis identified pyruvate dehydrogenase kinase 4 (PDK4) as a key downstream effector. TRPM7 upregulated PDK4, which was required for MAM assembly by stabilizing the GRP75‑VDAC1‑IP3R1 complex. TRPM7 activation triggered mitochondrial DNA release and subsequent activation of the cGAS‑STING pathway via PDK4, ultimately driving chondrocyte senescence. The TRPM7–PDK4–MAM axis represents a central pathogenic pathway in OA. Targeting TRPM7 channel function may serve as a novel therapeutic strategy for age‑related cartilage degeneration.