Procyanidin C1 activates Nrf2/HO-1 to preserve in vivo mitochondrial homeostasis and counter chondrocyte senescence in osteoarthritis
TL;DR
Findings establish a mechanistic link between PCC1, Nrf2/HO-1 activation and chondrocyte mitochondrial homoeostasis in osteoarthritis, and support Nrf2-directed senotherapies as a regenerative strategy to slow OA progression.
Abstract
Osteoarthritis (OA) is driven in part by chondrocyte senescence, mitochondrial dysfunction and chronic inflammation, yet disease-modifying therapies that directly target these ageing mechanisms are lacking. Here, we identify the grape-seed-derived polyphenol procyanidin C1 (PCC1) as a senotherapeutic candidate that preserves chondrocyte mitochondrial homoeostasis and attenuates senescence via activation of the Nrf2/HO-1 axis. In tert-butyl hydroperoxide-induced senescent chondrocytes, PCC1 reduced senescence-associated β-galactosidase activity, dampened secretion of senescence-associated secretory phenotype factors, restored mitochondrial membrane potential and dynamics, limited extracellular matrix degradation and suppressed NF-κB activation. Network pharmacology and transcriptomic analyses converged on Nrf2 as a potential molecular target of PCC1, which we validated using cellular thermal shift and drug affinity responsive target stability assays. Genetic silencing of Nrf2 abrogated PCC1-mediated protection in vitro, confirming that Nrf2 is required for the anti-senescent and mitochondrial effects of PCC1. In a surgically induced anterior cruciate ligament transection model of OA, PCC1 administration reduced cartilage erosion, preserved matrix organisation and subchondral bone structure, and mitigated synovial inflammation in Nrf2-sufficient mice, whereas Nrf2 deficiency abolished these benefits. Together, these findings establish a mechanistic link between PCC1, Nrf2/HO-1 activation and chondrocyte mitochondrial homoeostasis in osteoarthritis, and support Nrf2-directed senotherapies as a regenerative strategy to slow OA progression.