Curcumin alleviates cold stress-induced myocardial injury by regulating macrophage polarization through the STUB1/STAT1-STAT6-KLF4 signaling axis

Cold exposure is an important environmental risk factor for adverse cardiovascular outcomes, but the immune mechanisms linking cold stress to myocardial injury remain incompletely defined. Here, we investigated whether curcumin protects the cold-stressed heart by regulating macrophage polarization and the STUB1/STAT1-STAT6-KLF4 signaling network. Using a severe intermittent mouse cold-exposure model and a mild hypothermic BMDM cold-mimic system, we found that cold stress impaired cardiac function, increased inflammatory infiltration, and shifted macrophages toward a pro-inflammatory phenotype. Cold mimicry enhanced STUB1-STAT1 interaction and K48-linked STAT1 ubiquitination, reduced STAT1 abundance, and was accompanied by suppression of STAT6 activation and KLF4 transcription. Given the canonical antagonism between STAT1- and STAT6-driven macrophage programs, these changes are interpreted as context-specific co-disruption of STAT-family signaling under cold-induced proteostatic/inflammatory stress, rather than as evidence that STAT1 degradation alone directly suppresses STAT6. Curcumin reduced STUB1 abundance and STUB1-STAT1 engagement, attenuated STAT1 ubiquitination, restored STAT6 nuclear signaling and STAT6-dependent Klf4 transcription, and promoted anti-inflammatory macrophage polarization. In a species-matched Transwell co-culture system, curcumin-treated macrophages reduced inflammatory cytokine release and improved cardiomyocyte viability through paracrine effects. Macrophage-specific Klf4 deletion markedly attenuated curcumin-mediated immune remodeling and cardioprotection in vivo. These findings identify a macrophage-centered signaling network that contributes to cold stress-induced myocardial injury and position curcumin as an experimental immunomodulatory candidate. However, direct curcumin-STUB1 target engagement, systemic cytokine changes, optimal dosing/formulation, and human efficacy remain to be established.