Targeting EFHD2 may help cure nonalcoholic steatohepatitis

EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, plays a major immunomodulatory and inflammatory role in nonalcoholic steatohepatitis (NASH), reveals a study, noting how EFHD2 can be a promising target for NASH treatment.

In this study, hepatic EFHD2 expression was characterized in NASH patients and in two diet-induced NASH mouse models. Investigators used single-cell RNA sequencing and double-immunohistochemistry to examine EFHD2 expression patterns in NASH livers. They also assessed the effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma.

Finally, the investigating team analysed the molecular mechanisms underlying EFHD2 function and explored its potential as a therapeutic target via chemical and genetic examinations.

Significant elevations of EFHD2 expression were observed in hepatic macrophages/monocytes in both NASH patients and mice.

EFHD2 deletion, either globally or specifically in myeloid cells, resulted in improved hepatic steatosis and reduced immune cell infiltration while also inhibiting lipid peroxidation-induced ferroptosis and lessening fibrosis in NASH. In addition, deletion of EFHD2 prevented the development of NASH-related hepatocellular carcinoma.

The deletion of myeloid EFHD2 prevented TIM4+ resident Kupffer cells from being replaced by infiltrated monocytes and reversed the reductions in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH.

“Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane,” the investigators said. 

“This interaction mediates interferon-γ signalling, which triggers immune and inflammatory responses in macrophages during NASH,” they added. 

Furthermore, a novel stapled α-helical peptide targeting EFHD2 was found to be protective against NASH pathology in mice.