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Monocyte-Derived Macrophage Ferroptosis Amplifies Cholangitis in Primary Biliary Cholangitis via a Calpain/ACSL4 Axis

Tianfu Liu1, Yichen Huang2, Yizhe Wang3

  • 1Department of Hepatology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.

Biomedicines
|June 26, 2026
PubMed

Insights

Monocyte-derived macrophages (MoMFs) drive inflammation in primary biliary cholangitis (PBC) through ferroptosis. Targeting the calpain/ACSL4 axis offers a potential therapeutic strategy for this liver disease.

Area of Science:

  • Immunology
  • Cell Biology
  • Hepatology

Background:

  • Monocyte-derived macrophages (MoMFs) are key drivers of inflammation in primary biliary cholangitis (PBC).
  • The role of MoMF ferroptosis in amplifying PBC-associated cholangitis was previously unclear.
  • The calpain/ACSL4 axis was investigated as a potential regulator of MoMF ferroptosis.

Purpose of the Study:

  • To define ferroptotic programs in MoMFs within the context of PBC.
  • To evaluate the calpain/ACSL4 axis as a regulatory and therapeutic target in PBC.
  • To investigate the crosstalk between MoMFs and cholangiocytes in PBC pathogenesis.

Main Methods:

  • Analysis of human liver single-cell RNA sequencing data to identify MoMF ferroptosis signatures.
  • Multiplex immunofluorescence to detect ACSL4 and 4-hydroxynonenal (4-HNE) in human PBC tissues.
  • Utilized a 2OA-BSA-induced mouse model of PBC to assess liver injury, inflammation, and ferroptosis markers.
  • Pharmacological intervention with Liproxstatin-1 (Lip-1), rosiglitazone (ROSI), or PD150606 in mouse models and bone marrow-derived macrophages (BMDMs).

Main Results:

  • MoMFs were expanded in PBC livers, exhibiting strong ferroptosis signatures centered on ACSL4 and increased inflammatory crosstalk with cholangiocytes.
  • Human PBC tissues showed elevated ACSL4 and 4-HNE expression in CD11b+CD68+ cells.
  • PBC-like mice displayed increased oxidative stress (MDA, decreased GSH) and macrophage infiltration associated with ferroptosis markers.
  • Treatments with Lip-1, ROSI, or PD150606 ameliorated liver injury, reduced inflammation, and limited macrophage infiltration in PBC models.
  • PBC-derived BMDMs showed upregulated ACSL4 and CAPN1/2, increased sensitivity to ferroptosis inducers, and attenuated ferroptosis upon treatment with Ferrostatin-1 (Fer-1), ROSI, or PD150606.

Conclusions:

  • MoMF ferroptosis is a significant factor in the pathogenesis of primary biliary cholangitis.
  • The calpain/ACSL4 axis represents a pharmacologically tractable target that influences MoMF ferroptotic susceptibility.
  • Targeting this axis holds promise for mitigating macrophage-driven inflammatory liver injury in PBC.
Keywords:
ACSL4calpainferroptosismonocyte-derived macrophagesprimary biliary cholangitis

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