Abstract Body: Cardiovascular disease remains the leading cause of death worldwide. Because the adult human heart has minimal regenerative capacity, human pluripotent stem cell–derived cardiomyocytes (hPSC-CMs) represent a promising platform for cardiac repair. However, their immaturity remains a major barrier to therapeutic application.
Although previous studies have identified multiple regulators of cardiomyocyte maturation, including transcription factors and non-coding RNAs, the upstream regulatory networks that coordinate these processes remain incompletely understood. In particular, how RNA regulatory mechanisms integrate structural and metabolic maturation programs is largely unknown.
Here, we identify an RNA-binding protein–centered regulatory pathway that governs cardiomyocyte maturation through modulation of non-coding RNAs. Disruption of this pathway impairs key maturation hallmarks, including myosin isoform switching, metabolic remodeling, calcium handling, and mitochondrial function. Mechanistically, we uncover a previously uncharacterized long non-coding RNA, LINC C, as a critical downstream effector that modulates sarcomeric myosin switching. Importantly, loss of LINC C recapitulates the maturation defects observed in RBM24-deficient cardiomyocytes, supporting a functional linkage between RNA-binding protein–mediated regulation and lncRNA-dependent control of cardiomyocyte maturation.
Together, our findings reveal a previously unrecognized RNA regulatory axis that integrates non-coding RNA regulation with cardiomyocyte maturation. This study provides new mechanistic insights and identifies potential molecular targets for enhancing hPSC-CM maturation and advancing cardiac regenerative therapies.