Work

Integrated single-cell and experimental analyses identify HMGA1 as a candidate regulator of lactate-responsive metabolic–immune crosstalk in hepatocellular carcinoma

Year: 2026

Type: article

Abstract: Background Hepatocellular carcinoma (HCC) is characterized by extensive metabolic reprogramming, and immune evasion is closely linked to dysregulated lactate metabolism. However, the tumor-intrinsic mechanisms that translate extracellular lactate signals into Treg-associated immune remodeling remain poorly understood. Here, we integrated single-cell transcriptomic and multi-omics data to identify candidate mediators of lactate-linked metabolic–immune crosstalk in HCC. Methods Single-cell transcriptomic data were used to construct a cellular atlas of HCC and identify enriched immune subsets. Candidate genes were prioritized by intersecting Treg-related differentially expressed genes, TCGA-LIHC differential expression profiles, and a literature-curated set of lactylation-associated genes. Diagnostic performance and expression patterns were assessed in TCGA-LIHC and GSE25097, and survival associations were evaluated in TCGA-LIHC. Functional enrichment, protein–protein interaction network analysis, and virtual knockout simulations were also performed. For experimental validation, HepG2 cells were treated with sodium L-lactate, and HMGA1 expression and related metabolic and immunosuppressive readouts were assessed by RT-qPCR, western blotting, lactate assays, and ELISA. Conditioned media from these cultures were subsequently applied to Jurkat cells, and Treg-like responses were evaluated by RT-qPCR and flow cytometry. Results Tregs were enriched in HCC tissues. HMGA1, MKI67, and STMN1 emerged as candidate biomarkers, with HMGA1 showing the most consistent diagnostic performance across the two transcriptomic cohorts. Higher expression of each candidate was associated with poorer overall survival in TCGA-LIHC. In vitro, sodium L-lactate increased HMGA1 expression in HepG2 cells. HMGA1 knockdown reduced the expression of LDHA, GLUT1, MCT4, TGFB1, and PD-L1 and decreased TGF-β1 secretion. Conditioned medium from HMGA1-silenced, lactate-exposed HepG2 cells reduced FOXP3 expression and the proportion of CD4 + CD25+FOXP3 + Jurkat cells. Conclusion Integration with a lactylation-related gene set identified HMGA1, MKI67, and STMN1 as candidate biomarkers. Our experimental findings support a role for tumor cell-intrinsic HMGA1 in lactate-responsive metabolic and immunosuppressive signaling in HCC cells. The conditioned-medium experiments also suggest an associated Treg-like response in Jurkat cells. However, the present design neither establishes HMGA1 lactylation or a Treg-intrinsic function of HMGA1 nor distinguishes the effects of residual lactate from those of other soluble factors in the medium. Trial registration Not applicable.

Source: BMC Gastroenterology

DOI: 10.1186/s12876-026-05388-y

Authors: Wei Lai, Kewei Wang, Haojie Yu

Institutions: Zhejiang Chinese Medical University, First Affiliated Hospital Zhejiang University

Language: English

Topic: Cancer, Hypoxia, and Metabolism

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,190