TMEM39A acts as a novel profibrotic factor to activate hepatic stellate cells partially via the cell adhesion...

Hepatic stellate cell (HSC) transdifferentiation into myofibroblasts is a pivotal event in liver fibrosis, yet the underlying regulatory network remains elusive. This study explores the role of TMEM39A in HSC activation and its pro-fibrotic effects via the cell adhesion molecule (CAM) signaling axis.

An in vitro HSC activation model was established using TGF-β1-stimulated LX-2 cells, combined with TMEM39A knockdown and overexpression. Cell viability, migration, and apoptosis were assessed by CCK-8, wound healing, Transwell, and flow cytometry. Fibrotic marker expression was measured at both mRNA and protein levels. RNA sequencing and bioinformatics identified the CAM pathway as a candidate downstream effector, and its pharmacological inhibitor (Alicaforsen, an ICAM-1 antagonist) was used for validation.

TMEM39A expression correlated positively with HSC activation. Overexpression of TMEM39A promoted LX-2 viability, migration, and upregulation of fibrotic markers (α-SMA, COL1A1) while suppressing apoptosis, whereas knockdown reversed these effects. Mechanistically, TMEM39A activated the CAM axis with specific ICAM-1 elevation. Alicaforsen treatment partially inhibited the activation of HSCs and the expression of fibrosis markers induced by TMEM39A.

TMEM39A functions as a novel pro-fibrotic facilitator that promotes HSC activation at least partially through the CAM/ICAM-1 signaling axis. Our findings provide mechanistic insights into liver fibrosis and suggest TMEM39A and its downstream effectors as potential candidates for further therapeutic exploration, pending rigorous in vivo and clinical validation.