Xanthohumol inhibits extracellular matrix degradation via the Nrf2/PERK/ATF4/C/EBPβ pathway in osteoarthritis

Abstract Objectives This study aims to explore the therapeutic potential of Xanthohumol (XH) in mitigating osteoarthritis (OA) progression by inhibiting extracellular matrix (ECM) degradation. Specifically, it investigates the role of XH in reducing matrix metalloprotease-13 (MMP-13) activity and modulating the PRKR-like endoplasmic reticulum kinase/activating transcription factor 4 (PERK/ATF4) pathway while enhancing nuclear factor-erythroid 2-related factor 2 (Nrf2) activity. Methods In vitro experiments were conducted on OA chondrocytes (CTs) to evaluate MMP-13 production and collagen II expression following XH treatment. In vivo , XH was administered intraperitoneally, and cartilage degradation was assessed. Molecular analysis examined the expression of C/EBPβ, a downstream effector of the PERK/ATF4 pathway, and Nrf2 activity. Overexpression and knockdown experiments were performed to elucidate XH’s mechanistic effects. Results XH treatment reduced MMP-13 production by 46 % and increased collagen II expression by 38 % in vitro . In vivo , XH administration resulted in a 31 % decrease in cartilage degradation scores compared to controls. Mechanistically, XH decreased C/EBPβ expression and increased Nrf2 activity by 52 %. Overexpression of C/EBPβ or activation of the PERK/ATF4 pathway nullified XH’s protective effects, while Nrf2 knockdown abolished its benefits. Conclusions XH inhibits ECM degradation in OA by suppressing the PERK/ATF4/C/EBPβ pathway and activating Nrf2, demonstrating its potential as a low-cytotoxicity therapeutic agent for OA treatment. This approach offers a promising strategy for mitigating cartilage damage and advancing OA management.