Multiomics, multi-species profiling, and animal validation identify mitoxyperilysis as a conserved therapeutic target in metabolic dysfunction-associated steatohepatitis.
4 affiliations
- 1Tsinghua University Yuquan Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China.
- 2Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
- 3Tsinghua University Yuquan Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China. [email protected].
- 4Tsinghua University Yuquan Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China. [email protected].
Abstract
Background & aims
Metabolic dysfunction-associated steatohepatitis (MASH) is driven by complex intercellular communication and regulated cell death pathways. Mitoxyperilysis, a recently characterized form of regulated lytic cell death, remains poorly defined in MASH. Here, we integrated multiomics, cross-species transcriptomics, machine learning, and in vivo models to dissect mitoxyperilysis activation and its therapeutic relevance in MASH.Methods
Single‑cell and spatial transcriptomic datasets from mouse and human MASH livers were analyzed. Cell-cell communication was inferred using CellChat, and metabolite‑mediated cell-cell communication (mCCC) was assessed with MEBOCOST. Mitoxyperilysis activity was scored via AUCell and AddModuleScore. Eleven machine learning classifiers identified transcriptomic signatures distinguishing MASH from controls, and key regulators were subjected to in silico knockout (scTenifoldKnk). A choline‑deficient, L‑amino acid‑defined high‑fat diet (CDAHFD) mouse model was used for in vivo validation.Results
Single‑cell profiling revealed that mitoxyperilysis activity was highly enriched in myeloid cells, particularly monocyte‑derived macrophages (Mo‑Macrophages) and neutrophils, and was strongly induced by high‑fat high‑sucrose diet. CellChat and mCCC analyses demonstrated that Mo‑Macrophages served as central hubs of rewired inflammatory and metabolic crosstalk in MASH. Spatial transcriptomics confirmed the expansion of pro‑inflammatory hepatocyte subsets and conserved upregulation of mitoxyperilysis components (e.g. BAX, TLR4, NINJ1) in both mouse and human MASH. Cross‑species profiling across mouse, rat, hamster, non‑human primate, and human datasets demonstrated evolutionarily conserved activation of the entire mitoxyperilysis pathway. Machine learning identified Bax as the sole overlapping driver gene linking diet‑induced transcriptomic signatures to mitoxyperilysis. In silico Bax ablation perturbed lipid metabolism and immune pathways. In CDAHFD-induced MASH mice with typical pathological phenotypes, core mitoxyperilysis genes were transcriptionally upregulated, and Bax/Bid/Bak1 upregulation was validated at the protein level. While RhoA mRNA increased, total RhoA protein remained stable, with its ubiquitination elevated and activity suppressed.Conclusions
Mitoxyperilysis is an evolutionarily conserved, myeloid‑enriched pathway activated in MASH. Bax acts as a critical regulatory node, while RhoA is modulated via ubiquitination and functional suppression. Targeting this axis may provide a novel therapeutic strategy for MASH.
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BibTeX
@article{liu2026multiomics,
title = {{Multiomics, multi-species profiling, and animal validation identify mitoxyperilysis as a conserved therapeutic target in metabolic dysfunction-associated steatohepatitis.}},
author = {Hanjie Liu and Cong Qi and Ruixia Lu and Chuan An and Yangzhiyuan Wang and Shumiao Li and Rui Zhu and Xingzhong Feng and Huijuan Gao},
journal = {Biology direct},
year = {2026},
month = jul,
doi = {10.1186/s13062-026-00902-4},
url = {https://europepmc.org/article/MED/42908035},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Multiomics, multi-species profiling, and animal validation identify mitoxyperilysis as a conserved therapeutic target in metabolic dysfunction-associated steatohepatitis.
AU - Hanjie Liu
AU - Cong Qi
AU - Ruixia Lu
AU - Chuan An
AU - Yangzhiyuan Wang
AU - Shumiao Li
AU - Rui Zhu
AU - Xingzhong Feng
AU - Huijuan Gao
PY - 2026
DA - 2026/07/01
JO - Biology direct
DO - 10.1186/s13062-026-00902-4
UR - https://europepmc.org/article/MED/42908035
AB - Background & aims Metabolic dysfunction-associated steatohepatitis (MASH) is driven by complex intercellular communication and regulated cell death pathways. Mitoxyperilysis, a recently characterized form of regulated lytic cell death, remains poorly defined in MASH. Here, we integrated multiomics, cross-species transcriptomics, machine learning, and in vivo models to dissect mitoxyperilysis activation and its therapeutic relevance in MASH.Methods Single‑cell and spatial transcriptomic datasets from mouse and human MASH livers were analyzed. Cell-cell communication was inferred using CellChat, and metabolite‑mediated cell-cell communication (mCCC) was assessed with MEBOCOST. Mitoxyperilysis activity was scored via AUCell and AddModuleScore. Eleven machine learning classifiers identified transcriptomic signatures distinguishing MASH from controls, and key regulators were subjected to in silico knockout (scTenifoldKnk). A choline‑deficient, L‑amino acid‑defined high‑fat diet (CDAHFD) mouse model was used for in vivo validation.Results Single‑cell profiling revealed that mitoxyperilysis activity was highly enriched in myeloid cells, particularly monocyte‑derived macrophages (Mo‑Macrophages) and neutrophils, and was strongly induced by high‑fat high‑sucrose diet. CellChat and mCCC analyses demonstrated that Mo‑Macrophages served as central hubs of rewired inflammatory and metabolic crosstalk in MASH. Spatial transcriptomics confirmed the expansion of pro‑inflammatory hepatocyte subsets and conserved upregulation of mitoxyperilysis components (e.g. BAX, TLR4, NINJ1) in both mouse and human MASH. Cross‑species profiling across mouse, rat, hamster, non‑human primate, and human datasets demonstrated evolutionarily conserved activation of the entire mitoxyperilysis pathway. Machine learning identified Bax as the sole overlapping driver gene linking diet‑induced transcriptomic signatures to mitoxyperilysis. In silico Bax ablation perturbed lipid metabolism and immune pathways. In CDAHFD-induced MASH mice with typical pathological phenotypes, core mitoxyperilysis genes were transcriptionally upregulated, and Bax/Bid/Bak1 upregulation was validated at the protein level. While RhoA mRNA increased, total RhoA protein remained stable, with its ubiquitination elevated and activity suppressed.Conclusions Mitoxyperilysis is an evolutionarily conserved, myeloid‑enriched pathway activated in MASH. Bax acts as a critical regulatory node, while RhoA is modulated via ubiquitination and functional suppression. Targeting this axis may provide a novel therapeutic strategy for MASH.
SN - 1745-6150
ER -