The hypoxia-HIF-1α axis promotes myocardial infarction repair by inducing Galectin-9 palmitoylation and secretion via the TMED10/ZDHHC3 pathway to drive macrophage M2 polarization.

Cardiomyocyte-macrophage crosstalk is essential for post-infarction repair, with Galectin-9 (Gal-9) acting as a key immunoregulatory mediator. However, the mechanisms governing its expression and secretion remain unclear. Here, we show that hypoxia stabilizes HIF-1α in cardiomyocytes, driving Gal-9 expression. Pharmacological activation of HIF-1α with deferoxamine enhanced Gal-9 secretion, promoted macrophage polarization toward M2 phenotype, and improved cardiac function after myocardial infarction. These benefits were abrogated by HIF-1α inhibition or Gal-9 deletion, underscoring the HIF-1α-Gal-9 axis as a central regulator of cardiac healing. Mechanistically, Gal-9 secretion occurred via a TMED10-dependent, non-classical vesicular pathway. TMED10 interacted with Gal-9 through a glycan-independent interface to facilitate vesicle loading. Furthermore, Gal-9 underwent S-palmitoylation at Cys137, a modification required for membrane anchoring and secretion. ZDHHC3 was identified as the primary palmitoyl acyltransferase mediating this process; ZDHHC3 knockdown or Cys137 mutation markedly suppressed Gal-9 release. These findings define a novel regulatory network in which HIF-1α upregulates Gal-9, while TMED10 and ZDHHC3 coordinate its palmitoylation-dependent secretion. This pathway links hypoxic signaling to immune modulation, providing new mechanistic insight and therapeutic targets for post-infarction myocardial repair.