# Role of SMAD1/5/8 signaling in liver fibrosis

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $91,500

## Abstract

ABSTRACT
 Liver fibrosis and cirrhosis are widely prevalent globally and associated with high morbidity and mortality.
A hallmark of liver fibrosis is hepatic stellate cells (HSC) activation. While there are many transcriptional and
translational changes associated with HSC activation, how these changes are initiated and regulated is still not
well understood. We recently demonstrated that BMP-SMAD1/5/8 signaling in hepatocytes is not only the central
pathway that maintains iron homeostasis by regulating the iron hormone hepcidin, but also plays a protective
role in liver fibrosis, as mice with hepatocyte SMAD1/5/8 signaling deficiency display spontaneous liver fibrosis.
However, the mechanisms of hepatocyte SMAD1/5/8-mediated protection in liver fibrosis is not known. In
addition, the function of SMAD1/5/8 signaling in HSC is completely missing. The overall objective of this proposal
is to understand the role of SMAD1/5/8 signaling in hepatocytes and HSCs in liver fibrosis. My preliminary data
suggest a role for hepatocyte SMAD1/5/8 signaling in regulating the production of wntless to control secretion of
Wnt ligands, which have paracrine actions to activate HSCs. My data also suggest that intrinsic SMAD1/5/8
signaling within HSCs may also be protective against HSC activation and liver fibrosis. In Specific Aim I, I will
use in vitro and in vivo approaches to determine the role of hepatocyte wntless in HSC activation and liver fibrosis
in hemochromatosis and NASH models. I will also perform secretomics to identify the hepatocytes secreted
paracrine modulators that activate HSCs. In Specific Aim II, I will used primary HSCs and HSC specific
conditional knockout mice to investigate the intrinsic role of SMAD1/5/8 in HSC activation and liver fibrosis. This
proposal will not only fill in the gaps in understanding the pathology of liver fibrosis in hemochromatosis but will
also advance the liver fibrosis field more broadly by providing new insights into hepatocyte-HSCs intercellular
communication and HSCs biology, more importantly, will pave the way for new clinical treatments for liver fibrosis
and cirrhosis. My long-term career goal is to successfully establish a research group and obtain a tenure-track
faculty position in a leading academic or hospital-based research institute. My future research goals are to bridge
the gaps between iron disorders and chronic liver diseases through investigating the direct biological
mechanisms by combining my expertise in iron homeostasis with the new training opportunities in liver
histopathology, gene editing and proteomics techniques described in this proposal.

## Key facts

- **NIH application ID:** 10984560
- **Project number:** 1K99DK138293-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Xia Xiao
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $91,500
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984560

## Citation

> US National Institutes of Health, RePORTER application 10984560, Role of SMAD1/5/8 signaling in liver fibrosis (1K99DK138293-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10984560. Licensed CC0.

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