Multi-cohort and single-nucleus transcriptomics identify a five-gene lactylation-related panel and a disease-dependent hepatocyte glycolysis-lactylation-related expression program in metabolic dysfunction-associated steatohepatitis.
4 affiliations
- 1Shanxi Bethune Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China.
- 2Department of Pharmacology, Shanxi Medical University, Taiyuan, 030600, China.
- 3Shanxi University of Medicine, Fenyang, 032200, China.
- 4Shanxi Bethune Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China. [email protected].
Abstract
Lysine lactylation couples glycolytic flux to protein and chromatin regulation, but the expression landscape of lactylation-related genes (LRGs) in metabolic dysfunction-associated steatohepatitis (MASH) has not been mapped. We analysed 320 LRGs across eight bulk, single-nucleus and spatial transcriptomic datasets. Sixty-six LRGs were differentially expressed in a merged training cohort (51 controls, 49 MASH). A severity-anchored funnel and four machine-learning algorithms then converged on a five-gene panel (SIRT1, CEBPZ, TKT, RPL14, CD2BP2). A neural network on the panel reached a nested cross-validated AUC of 0.89 and detected MASH against histologically normal liver in a classifier-external cohort (AUC 0.90-0.97). The panel did not separate MASH from simple steatosis (NAFL), a boundary shared by all four benchmarked signatures (AUC 0.50-0.70). In 265,271 nuclei from 48 livers, the LRG expression program localised to hepatocytes and rose most significantly in Hep3, a sterol- and lipid-biosynthetic state that expanded 7.2-fold in MASH. Hepatocyte transcriptomic LRG scores tracked glycolysis across MASH patients (rho = 0.93, n = 19) but not across controls (rho = 0.01, n = 23; P = 1.3 × 10⁻⁶ for the difference). This disease dependence exceeded that of 1,000 expression-matched random gene sets. Hep3 and glycolysis signals were oriented centrilobularly in Visium sections from four donors. The panel offers a transcriptomic MASH detection axis, and the Hep3-centred program a hypothesis for hepatic lactylation that lactylomic profiling can now test.
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BibTeX
@article{mi2026multicohort,
title = {{Multi-cohort and single-nucleus transcriptomics identify a five-gene lactylation-related panel and a disease-dependent hepatocyte glycolysis-lactylation-related expression program in metabolic dysfunction-associated steatohepatitis.}},
author = {Yang Mi and Ziang Liu and Xiaolong Li and Xuchen Zhao and Wei Xue and Zongyuan Che and Yulin Feng and Ruijun Ru and Rongjia Zhang and Yanzhang Tian},
journal = {Functional \& integrative genomics},
year = {2026},
month = oct,
doi = {10.1007/s10142-026-02079-5},
url = {https://europepmc.org/article/MED/42955459},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Multi-cohort and single-nucleus transcriptomics identify a five-gene lactylation-related panel and a disease-dependent hepatocyte glycolysis-lactylation-related expression program in metabolic dysfunction-associated steatohepatitis.
AU - Yang Mi
AU - Ziang Liu
AU - Xiaolong Li
AU - Xuchen Zhao
AU - Wei Xue
AU - Zongyuan Che
AU - Yulin Feng
AU - Ruijun Ru
AU - Rongjia Zhang
AU - Yanzhang Tian
PY - 2026
DA - 2026/10/29
JO - Functional & integrative genomics
DO - 10.1007/s10142-026-02079-5
UR - https://europepmc.org/article/MED/42955459
AB - Lysine lactylation couples glycolytic flux to protein and chromatin regulation, but the expression landscape of lactylation-related genes (LRGs) in metabolic dysfunction-associated steatohepatitis (MASH) has not been mapped. We analysed 320 LRGs across eight bulk, single-nucleus and spatial transcriptomic datasets. Sixty-six LRGs were differentially expressed in a merged training cohort (51 controls, 49 MASH). A severity-anchored funnel and four machine-learning algorithms then converged on a five-gene panel (SIRT1, CEBPZ, TKT, RPL14, CD2BP2). A neural network on the panel reached a nested cross-validated AUC of 0.89 and detected MASH against histologically normal liver in a classifier-external cohort (AUC 0.90-0.97). The panel did not separate MASH from simple steatosis (NAFL), a boundary shared by all four benchmarked signatures (AUC 0.50-0.70). In 265,271 nuclei from 48 livers, the LRG expression program localised to hepatocytes and rose most significantly in Hep3, a sterol- and lipid-biosynthetic state that expanded 7.2-fold in MASH. Hepatocyte transcriptomic LRG scores tracked glycolysis across MASH patients (rho = 0.93, n = 19) but not across controls (rho = 0.01, n = 23; P = 1.3 × 10⁻⁶ for the difference). This disease dependence exceeded that of 1,000 expression-matched random gene sets. Hep3 and glycolysis signals were oriented centrilobularly in Visium sections from four donors. The panel offers a transcriptomic MASH detection axis, and the Hep3-centred program a hypothesis for hepatic lactylation that lactylomic profiling can now test.
SN - 1438-793X
SN - 1438-7948
ER -