# MCM7 promotes liver fibrosis by transcriptionally regulating IL11 via the SHCBP1-RACGAP1-STAT3 axis

## TL;DR

MCM7 in liver cells worsens liver fibrosis by boosting IL11 production through a specific protein pathway, offering a new target for treatment.

## Contribution

MCM7's role in promoting liver fibrosis via SHCBP1-RACGAP1-STAT3-mediated IL11 transcription is newly identified.

## Key findings

- MCM7 overexpression in hepatocytes accelerates liver fibrosis in mouse models.
- MCM7 interacts with SHCBP1 to activate IL11 transcription through RACGAP1 and STAT3.
- Blocking IL11 reduces liver fibrosis caused by MCM7 overexpression.

## Abstract

Liver fibrosis is driven by the persistent activation of hepatic stellate cells (HSCs) through inflammatory factors released from various cell types, including stressed hepatocytes, yet the underlying mechanisms are not fully understood. Here, we show that minichromosome maintenance complex component 7 (MCM7) is predominantly upregulated in hepatocytes of liver fibrosis mouse models and in liver cirrhosis patients. Hepatocyte-specific overexpression of MCM7 accelerates fibrosis progression, while its knockdown mitigates it in Schistosoma japonicum- and CCl4-induced fibrosis models. Mechanistically, MCM7 interacts with SHCBP1, promoting IL11 transcription via the SHCBP1-RACGAP1-STAT3 axis. Moreover, neutralizing IL11 significantly attenuated the enhanced activation of HSCs induced by MCM7 overexpression in vitro. Additionally, recombinant human IL11 (rhIL11), which effectively inhibits endogenous IL11 signaling, significantly attenuated the exacerbation of liver fibrosis driven by MCM7 overexpression in vivo. These findings identify MCM7 in hepatocytes as a key regulator of HSC activation through IL11 and highlight its potential as a therapeutic target for liver fibrosis treatment.

Liver fibrosis conditions induce upregulation of MCM7 and SHCBP1 in hepatocytes. Elevated MCM7 promotes the interaction between SHCBP1 and RACGAP1, which in turn facilitates the binding of RACGAP1 to STAT3 and induces its phosphorylation. Phosphorylated STAT3 translocates to the nucleus, activating transcription of the IL11 gene. Secreted IL11 acts in a paracrine manner to enhance hepatic stellate cell activation, further exacerbating liver fibrosis.

Liver fibrosis conditions induce upregulation of MCM7 and SHCBP1 in hepatocytes. Elevated MCM7 promotes the interaction between SHCBP1 and RACGAP1, which in turn facilitates the binding of RACGAP1 to STAT3 and induces its phosphorylation. Phosphorylated STAT3 translocates to the nucleus, activating transcription of the IL11 gene. Secreted IL11 acts in a paracrine manner to enhance hepatic stellate cell activation, further exacerbating liver fibrosis.