LNCHC directly binds and regulates YBX1 stability to ameliorate metabolic dysfunction‐associated steatotic liver disease progression

Background and Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) represents the foremost cause of chronic liver disease, yet its underlying mechanisms remain elusive. Our group previously discovered a novel long non‐coding RNA (lncRNA) in rats, termed lncHC and its human counterpart, LNCHC. This study aimed to explore the role of LNCHC in the progression of MASLD. Methods RNA‐binding proteins bound to LNCHC were searched by mass spectrometry. The target genes of LNCHC and Y‐Box binding protein 1 (YBX1) were identified by RNA‐seq. MASLD animal models were utilised to examine the roles of LNCHC, YBX1 and patatin‐like phospholipase domain containing 3 (PNPLA3) in MASLD progression. Results Here, we identified LNCHC as a native restrainer during MASLD development. Notably, LNCHC directly binds YBX1 and prevents protein ubiquitination. Up‐regulation of YBX1 then stabilises PNPLA3 mRNA to alleviate lipid accumulation in hepatocytes. Furthermore, both cell and animal studies demonstrate that LNCHC, YBX1 and PNPLA3 function to improve hepatocyte lipid accumulation and exacerbate metabolic dysfunction‐associated steatohepatitis development. Conclusions In summary, our findings unveil a novel LNCHC functionality in regulating YBX1 and PNPLA3 mRNA stability during MASLD development, providing new avenues in MASLD treatment.