Osteoarthritis (OA) is increasingly recognized as a metabolically influenced joint disorder, driven in part by oxidative stress and ferroptosis. In this study, we investigated the role of cysteine metabolism in OA pathogenesis by integrating transcriptomic data across species and validating findings through proteomics analysis of human OA cartilage. We observed consistent dysregulation of the cysteine/glutathione axis and ferroptosis-related pathways, including altered expression of GPX4, SLC7A11, and TFRC. In in vitro study, cysteine deprivation in IL-1β-stimulated chondrocytes triggered hallmark features of ferroptosis—diminished viability, glutathione depletion, and increased lipid peroxidation—all of which were reversed by L-cysteine supplementation. In a surgery-induced OA mouse model, L-cysteine treatment significantly reduced cartilage degeneration and restored redox homeostasis. Based on these findings, we propose the rational design of therapeutic peptides targeting cysteine metabolism and ferroptosis pathways. We are working on developing and synthesizing peptides that mimic or enhance the function of cysteine transporters, upregulate antioxidant defenses, or inhibit ferroptosis triggers, with modification strategies to improve cartilage targeting and stability. These efforts aim to overcome the limitations of small-molecule or amino acid-based therapies and establish a new class of peptide-based disease-modifying treatments for OA, bridging redox metabolism and precision peptide therapeutics.