[en] Highlights: • MALAT1 was up-regulated in CPCs in hypoxia conditions. • MALAT1 suppression inhibited CPCs proliferation and migration after hypoxia-inducing stimuli. • MALAT1 modulated CPCs proliferation and migration through MALAT1/miR-125/JMJD6 axis under hypoxia conditions. The death of cardiomyocytes after myocardial infarction (MI) often leads to ventricular remodeling as well as heart failure (HF). The cardiac progenitor cells (CPCs) have the ability to regenerate functional heart muscle in patients after MI, which provides a promising method for MI-induced HF therapy. However, to date, CPCs can easily lose their proliferation ability in the infarcted myocardium. Therefore, exploring the mechanism for CPC proliferation is essential for CPC-based therapy in MI-induced HF. A previous study indicated that a hypoxic environment is essential for CPC proliferation, but the mechanism is not yet clear. In this work, we discovered that CoCl₂-induced hypoxia can promote CPC proliferation and migration. Additionally, long non-coding RNA MALAT1 expression was significantly up-regulated in the CoCl₂-induced hypoxia CPC model. MALAT1 suppression inhibited CPC proliferation and migration under hypoxic conditions. In addition, MALAT1 acted as a sponge for miR-125. The miR-125 inhibitor restored the proliferation and migration potentials of CPCs after a MALAT1 knockdown in hypoxia. A further study demonstrated that JMJD6 was a target of miR-125 whose expression was negatively regulated by miR-125. JMJD6 knockdown blocked miR-125 inhibitor's protective effect on CPC function in hypoxia. Ultimately, our finding demonstrated that MALAT1 can modulate CPC proliferation and migration potential through the miR-125/JMJD6 axis in hypoxia. Our finding provided a new regulatory mechanism for CPC proliferation in hypoxia, which provided a new target for MI-induced HF therapy.