# Myeloid loss of scaffolding protein menin promotes liver fibrosis via H3K36me3 reprogramming

## TL;DR

This study shows that losing the Menin protein in myeloid cells worsens liver fibrosis by altering histone marks, suggesting new treatment approaches.

## Contribution

The study identifies Menin's role in liver fibrosis via H3K36me3 regulation and proposes H3K36me3 as a therapeutic target.

## Key findings

- Menin loss in myeloid cells promotes liver fibrosis by modulating Kupffer cells and hepatic stellate cells.
- Menin/SETD2 regulates liver fibrosis through H3K36me3-dependent control of IL-10 and SMAD7 expression.
- JIB-04, an H3K36me3 agonist, alleviates fibrosis by reactivating IL-10 in Men1 or Setd2-deleted cells.

## Abstract

Menin, encoded by the Men1 gene, is a scaffold protein broadly involved in regulating the cell phenotype through multiple histone modifications. Here, we discuss how menin contributes to liver macrophage (MAC) and hepatic stellate cell (HSC) fate determination, placing this contribution in the context of liver fibrosis pathogenesis. We revealed that Men1 loss promoted CCL4- or high-fat diet-induced liver fibrosis. Menin regulated liver fibrogenesis primarily by modulating the activation of Kupffer cells (KCs)/HSCs rather than hepatocytes. The myeloid cell-specific knockout of Setd2 but not Kmt2a mimicked the phenotype of Men1 deletion. Menin/SETD2 suppressed the regeneration and activation of KCs by regulating IL-10 pathway activity through H3K36me3. In addition, the menin/SETD2/PPARγ complex coregulated SMAD7 expression through H3K36me3 in HSCs. JIB-04, an H3K36me3 agonist, effectively suppressed KC activation induced by Men1 or Setd2 deletion by reactivating IL-10 expression and further alleviated CCL4-induced liver fibrosis symptoms. Our results provide an interesting proof-of-concept for the therapeutic targeting of H3K36me3 remodeling to block liver fibrosis.