<scp>HSPA12B</scp> Protects Against Age‐Related Endothelial Cell Senescence by Regulating <scp>STING</scp> Degradation

Cardiovascular diseases remain the leading cause of mortality worldwide, with aging as a major risk factor. Endothelial cell (EC) dysfunction, driven by cellular senescence, is central to age-related cardiomyopathy. Despite its clinical significance, the molecular mechanisms underlying endothelial senescence remain incompletely defined. In this study, we observed that the expression of the endothelial-specific gene heat shock protein family A member 12B (HSPA12B) declines significantly with age. HSPA12B deficiency in mice accelerates age-related EC senescence and cardiac dysfunction, whereas HSPA12B overexpression mitigates EC senescence, highlighting its protective role against vascular aging. Mechanistically, HSPA12B deficiency impairs X-box binding protein 1 (XBP1) transcriptional activity and consequently reduces the expression of its downstream target genes suppressor/enhancer of lin-12-like (SEL1L) and HMG-CoA reductase degradation protein-1 (HRD1). This disruption compromises endoplasmic reticulum-associated degradation (ERAD) of Stimulator of interferon genes (STING), resulting in persistent activation of the cyclic GMP-AMP synthase (cGAS)-STING pathway, a critical driver of EC senescence. In contrast, increased HSPA12B expression enhances XBP1 nuclear translocation and upregulates SEL1L and HRD1, thereby attenuating age-related STING activation. Importantly, pharmacological inhibition of STING reversed the senescent phenotype caused by HSPA12B deficiency. Similarly, enhancing XBP1 activity restored SEL1L and HRD1 expression, reduced STING activation, and alleviated EC senescence. Conversely, SEL1L deficiency or HRD1 inhibition exacerbated STING activation and abolished the protective effects of HSPA12B. Collectively, these findings reveal a previously unrecognized role for HSPA12B in preserving endothelial homeostasis during aging by regulating XBP1-mediated ER-associated degradation of STING and highlight HSPA12B as a potential therapeutic target for age-related cardiovascular dysfunction.