First, phenotype and stage matter: early OA marked by adaptive UPR imbalance may benefit most from ER-stress buffering and iHSP70 up-regulation; obesity/metabolic OA might require strategies that reduce eHSP70-TLR signaling and restore insulin-linked HSP70 expression; fibrotic, pain-dominant phenotypes could need TRAP1/HSP90-axis interference alongside anti-fibrotics. This evidence concerns the gene HSPA1A and obesity due to melanocortin 4 receptor deficiency.