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Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro\u2010fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (\u0394EGFR mice). Here, we have analyzed the response of WT and \u0394EGFR mice to chronic treatment with carbon tetrachloride (CCl\n                    <jats:sub>4<\/jats:sub>\n                    ), which induces a pro\u2010inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010treated \u0394EGFR mice when compared with CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from\n                    <jats:italic>in vitro<\/jats:italic>\n                    experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro\u2010fibrotic and pro\u2010inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase\u2010dependent actions in hepatocytes that reveal its key role in chronic liver damage. \u00a9 2024 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6299","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T03:12:06Z","timestamp":1718334726000},"page":"482-495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The hepatocyte epidermal growth factor receptor (\n                    <scp>EGFR<\/scp>\n                    ) pathway regulates the cellular interactome within the liver fibrotic 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