ArticleHepatology communications2026
A PNPLA3-NACC1-RIPK3 pathway mediates macrophage necroptosis and inflammation in MASLD.
Article in Hepatology communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 1 paper.
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1 citing paper in PubMed.
- Erratum: A PNPLA3-NACC1-RIPK3 pathway mediates macrophage necroptosis and inflammation in MASLD.Hepatology communications · 2026Article
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- Erratum issued
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9 authors.
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Abstract
backgroundThe 148M variant of PNPLA3 is a major genetic risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), yet its macrophage-specific role remains unclear. We investigated how PNPLA3-148M alters macrophage behavior and multicellular liver pathology under lipotoxic stress.
methodsWe used a human induced pluripotent stem cell (iPSC)-derived multicellular liver culture comprising hepatocytes, hepatic stellate cells (HSCs), and isogenic macrophages that differed only at PNPLA3 (148M vs. 148I). Cultures were exposed to lipotoxic conditions to induce MASLD. We quantified inflammatory cytokines, oxidative stress, hepatocyte lipid accumulation, and HSC activation. Macrophage death pathways were profiled (apoptosis, pyroptosis, necroptosis), with emphasis on RIPK3 expression and phosphorylation. Downstream effects on hepatocytes and HSCs were assessed.
resultsUnder lipotoxic stress, 148M macrophages amplified MASLD-like features. PNPLA3 transcripts were induced in macrophages-rising in iPSC-derived macrophages from lipotoxic cultures, and in Kupffer cells isolated from murine MASLD. Single-cell RNA-seq further confirmed PNPLA3 expression in human liver macrophage clusters, in addition to hepatocytes and HSCs. Although PNPLA3 mRNA was comparable between genotypes, 148M macrophages displayed higher PNPLA3 protein and increased necroptosis, evidenced by elevated RIPK3 expression and phosphorylation without changes in apoptosis or pyroptosis. Integrative analyses identified NACC1 as a key transcriptional regulator of RIPK3, with NF-κB-linked upregulation of NACC1 in 148M macrophages. NACC1 inhibition (genetic or NIC3) reduced RIPK3, suppressed necroptosis, and lowered pro-inflammatory cytokine secretion. NIC3 additionally decreased hepatocyte lipid accumulation and ATP and diminished HSC activation markers.
conclusionsThe PNPLA3 148M variant promotes MASLD through a macrophage-specific NF-κB-NACC1-RIPK3 axis that enhances necroptosis and inflammatory signaling, thereby exacerbating hepatocyte steatosis and HSC activation. NACC1 emerges as a tractable therapeutic target for genetically at-risk individuals.
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