The p21 resilience network: a conceptual framework linking senescence to ferroptosis and cuproptosis resistance

We reconceptualize p21 as the master regulator of a "resilience network" that empowers cancer cells to defy therapy. Beyond cell cycle arrest, p21 orchestrates a multi-faceted defense, suppressing ferroptosis and cuproptosis by governing redox and metal ion homeostasis. This perspective demands a therapeutic paradigm shift: targeting the p21 network is essential to dismantle this evolved survival machinery and force durable tumor regression in resistant cancers.