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Therefore, stage-specific intervention is critical—moderate activation of autophagy is advocated in early KOA to counteract age- or stress-induced autophagy decline, while in subsets of mid-to-late KOA characterized by pathological autophagy overactivation, transient inhibition may be warranted to prevent autophagic cell death ( Pharmacological autophagy inducers, such as rapamycin (an mTOR inhibitor) and metformin (an AMPK activator), enhance cytoprotective autophagy primarily by suppressing the PI3K/AKT/mTOR pathway and/or activating the AMPK/mTOR axis