Tregs With High CD29 Expression Promote Cell Adhesion and Contribute to the Malignant Transformation of MASLD.

BACKGROUND AND AIM: Regulatory T cells (Tregs) are highly enriched in the metabolic dysfunction-associated steatotic liver disease (MASLD) microenvironment, but their role in driving metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC) remains unclear. Here, it is demonstrated that integrin β1 (ITGβ1, CD29) expression is upregulated by Tregs, enhancing cell adhesion and driving the malignant transformation of MASLD.

METHODS

A MASLD mouse model was established via high-fat diet (HFD) and 2-acetylamino fluorene (2-AAF). Single-cell RNA sequencing (scRNA-seq) and flow cytometry were employed to quantitatively analyse the distribution of T lymphocytes and their subsets in the livers of MASLD mice, with particular focus on the Treg subset. Subsequently, a Treg subset with high CD29 expression was identified through unsupervised clustering analysis. Further validation using single-cell sequencing data and in vitro functional assays demonstrated that Tregs promote cell adhesion by upregulating CD29, thereby driving the progression of MASH to HCC. Finally, the effect of CD29 knockdown on the Tregs-induced malignant transformation of MASLD was studied.

RESULTS

MASLD mice showed reduced hepatic T lymphocytes, imbalanced CD8+/CD4+ T ratios, and increased Tregs despite lower CD4+ T proportions. Two Treg subsets were identified, one with high CD29 that was overexpressed in HCC; Tregs promoted cell adhesion via CD29 to drive MASH-HCC transition, and CD29 knockdown attenuated this effect.

CONCLUSIONS

Tregs promote cell adhesion through CD29 upregulation, inducing the malignant transformation of MASLD. Targeting CD29 may offer a potential strategy for preventing HCC in patients with MASH.