Advanced Oxidation Protein Products exacerbate osteoarthritis progression by disrupting stress granules assembly via endoplasmic reticulum stress

Recent studies indicate that levels of Advanced Oxidation Protein Products (AOPPs) in the synovial fluid of osteoarthritis (OA) patients positively correlate with disease severity. AOPPs are not only biomarkers of oxidative damage but also effector molecules that drive disease progression. Although stress granules (SGs) play a central role in cellular stress response, their function in AOPPs-mediated OA progression remains unclear. This study is the first to reveal the signaling pathway through which AOPPs exacerbate OA by disrupting SGs assembly. We found that AOPPs disrupt intracellular calcium homeostasis, induce endoplasmic reticulum stress (ERS), and subsequently activate the PERK-ATF4-CHOP signaling axis. This activation upregulates the key regulator GADD34. Increased GADD34 leads to abnormal dephosphorylation of eIF2α, which hinders the nucleocytoplasmic transport of the core SGs protein TIA-1 and ultimately disrupts SGs assembly. Further experiments demonstrated that the GADD34-specific inhibitor Sephin1 effectively restores eIF2α phosphorylation and rebuilds SGs formation, significantly alleviating OA progression. Moreover, we innovatively developed a hyaluronic acid microneedles transdermal delivery system loaded with Sephin1. In vivo studies confirmed that its efficacy is comparable to intra-articular injection, while offering the advantages of being minimally invasive and safe. This research not only elucidates a novel mechanism of the AOPPs-ERS-SGs axis in OA pathogenesis but also provides a new therapeutic target and delivery strategy for OA treatment. • AOPPs disrupt stress granules assembly by impairing TIA1 nucleocytoplasmic transport. • AOPPs activate PERK pathway and upregulate GADD34 in osteoarthritic progression. • Sephin1 inhibits GADD34, restores stress granules, and alleviates AOPPs-induced cartilage damage. • Microneedles-based transdermal delivery of Sephin1 effectively treats osteoarthritis in vivo.