Doxorubicin-induced cardiotoxicity: SESN2-directed FBXO7 ubiquitination of CRY1 restores glycolytic homeostasis.

Doxorubicin (DOX), a cornerstone anthracycline antineoplastic agent, induces cumulative, dose-limiting cardiotoxicity that remains a major barrier to its clinical use. Accumulating evidence suggests that maladaptive metabolic remodeling-particularly loss of glycolytic competence-contributes centrally to DOX-induced cardiac dysfunction. Here we identify Sestrin 2 (SESN2) as a cardiomyocyte-intrinsic metabolic safeguard that maintains glycolytic integrity under anthracycline stress. Integrative transcriptomic analyses reveal that SESN2 is suppressed in DOX-injured myocardium and is closely aligned with glycolytic gene programs. In murine models of acute and chronic cardiotoxicity, DOX reduces cardiac SESN2 expression concomitant with broad repression of glycolytic function; cardiomyocyte-restricted Sesn2 overexpression restores glycolytic activity, dampens inflammation, and oxidative stress, and preserves systolic function, whereas Sesn2 depletion precipitates glycolytic collapse and exacerbates cardiac dysfunction. Mechanistically, we define cryptochrome 1 (CRY1) as a critical downstream effector of SESN2-driven metabolic control. SESN2 directly associates with CRY1 and promotes FBXO7-dependent ubiquitination at Lys159, accelerating proteasomal degradation of CRY1 and thereby derepressing glycolytic programs. Consistently, cardiac Cry1 knockdown rescues glycolytic defects and functional decline elicited by Sesn2 loss in vivo. Together, these findings establish a SESN2-FBXO7-CRY1 proteostasis-metabolism axis that links anthracycline chemical stress to glycolytic failure and nominate SESN2-centered interventions as a rational strategy to restore myocardial metabolic homeostasis and mitigate DOX cardiomyopathy.