Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide, affecting approximately 250 million individuals. Mechanical imbalance serves as both its primary driving force and pathological hallmark. Mechanobiology-based interventions remain constrained by an insufficient understanding of how chondrocytes perceive and adapt to aberrant mechanical environments. Here, we review the cascading mechanisms linking mechanical imbalance to cellular dysfunction in OA and emerging therapeutic strategies targeting these mechanobiological processes. At the biomechanical level, joint mechanical imbalance encompasses both abnormal exogenous loading (trauma, obesity, joint deformity) and alterations in extracellular and pericellular matrix properties, with spatial heterogeneity and temporal dynamics throughout disease progression. At the cellular level, chondrocytes perceive mechanical signals through primary mechanosensors, including mechanosensitive ion channels (Piezo1/2, TRPV4), integrin-focal adhesion complexes, and primary cilia. These signals initiate Ca2+ signaling and cytoskeletal remodeling and converge on signaling and transcriptional regulators, including NF-κB, Wnt/β-catenin, YAP, and MAPK, ultimately contributing to cell death, cellular senescence, matrix degradation, and sustained inflammation. From a therapeutic perspective, we summarize mechanobiologically informed strategies, including macromechanical modulation, signaling regulation, and advanced biomaterial platforms for mechanical support, viscoelastic regulation, lubrication, drug delivery, and immunomodulation, aimed at restoring mechanical homeostasis and supporting tissue regeneration.
