NDRG2 orchestrates structural and functional adaptation for cardioprotection during mammalian hibernation.

Cold stress severely challenges the cardiovascular system under distinct physiological contexts: environmental cold exposure, systemic hypothermia, and donor heart cold preservation. Yet, hibernating mammals remarkably tolerate these extremes without evident injury, offering ideal models to decipher cardiac cold adaptation. Here, we induced hibernation in Syrian hamsters, a mammalian hibernator, under controlled cold stress (4 °C ambient, ∼5 °C body temperature). Notably, torpid Syrian hamsters exhibited reversible cardiac hypertrophy, a process verified to represent physiological rather than pathological remodeling that enhances cardiac cold resilience. We further identified NDRG2 as a key effector, and its overexpression in non-hibernating mice recapitulated this adaptive phenotype, promoting physiological cardiac hypertrophy, attenuating pathological remodeling, and improving cardiac cold tolerance. Mechanistically, NDRG2 orchestrates a fatty acid metabolic program to mitigate cold-induced cardiac injury during hibernation. Collectively, our work identifies the NDRG2-fatty acid axis as a central mechanism integrating structural, metabolic, and functional adaptation to cold stress, providing unique insights into cardioprotection.