# Human umbilical cord-derived mesenchymal stem cells ameliorate non-alcoholic fatty liver disease via activating TFEB-mediated autophagy in male mice

## TL;DR

Human umbilical cord stem cells help treat fatty liver disease in mice by boosting a process called autophagy, which clears fat buildup in the liver.

## Contribution

This study reveals that hUC-MSCs treat NAFLD by activating TFEB-mediated autophagy, a novel mechanism for their therapeutic effect.

## Key findings

- hUC-MSCs reduced liver fat and inflammation in NAFLD mice.
- hUC-MSCs restored autophagy via the AMPK-mTOR-TFEB pathway in both mice and HepG2 cells.
- TFEB nuclear translocation was promoted by hUC-MSCs, and TFEB knockdown reduced their beneficial effects.

## Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid accumulation in hepatocytes and defective autophagy has been implicated in its pathogenesis. Human umbilical cord-derived MSCs (hUC-MSCs) have shown therapeutic potential in treating NAFLD, while underlying molecular mechanisms remained largely unknown.

Male C57BL/6J mice fed a choline-deficient high fat diet (CD-HFD) and HepG2 cells exposed to palmitic acid/oleic acid were established as in vivo and in vitro models of NAFLD, respectively. Both models were subjected to treatment with human umbilical cord-derived MSCs (hUC-MSCs). Lipid content, proinflammatory cytokines, fibrosis markers and the hepatic transcriptome were assessed to determine the effect of hUC-MSCs.

Here, hUC-MSCs decreased hepatic lipid content and alanine aminotransferase/aspartate aminotransferase levels, as well as attenuated inflammation and fibrosis in choline-deficient high-fat diet (CD-HFD)-induced NAFLD mice. Mechanistically, hUC-MSCs restored impaired autophagic flux and mitigated liver steatosis through the AMPK-mTOR-TFEB pathway in both NAFLD mice and oleic acid/palmitic acid-induced “fatty” HepG2 cells. Of note, hUC-MSCs have been found to promote nuclear translocation of TFEB in PA/OA-induced HepG2 cells. Additionally, TFEB knockdown partially attenuated the effect of hUC-MSCs on enhancing autophagy and lipid metabolism in vitro.

This study suggests that hUC-MSCs represent a potential therapeutic approach to treating NAFLD through activating TFEB-mediated autophagy.

The online version contains supplementary material available at 10.1186/s13287-025-04855-9.