Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLD
Non-alcoholic fatty liver disease (NAFLD) is a global health challenge characterized by complex pathogenesis and limited therapeutic options. Emerging evidence highlights PANoptosis—a coordinated interplay of pyroptosis, apoptosis, and necroptosis—as a critical driver of metabolic and immune dysregu...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Immunobiology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171298525000439 |
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| author | Feng Tian Yuqi Zhao Xinyang He Yu Zhang Minxuan Hu Yiwei Liang Ziyou Tian Yaxian Gao Yongwei Wang |
| author_facet | Feng Tian Yuqi Zhao Xinyang He Yu Zhang Minxuan Hu Yiwei Liang Ziyou Tian Yaxian Gao Yongwei Wang |
| author_sort | Feng Tian |
| collection | DOAJ |
| description | Non-alcoholic fatty liver disease (NAFLD) is a global health challenge characterized by complex pathogenesis and limited therapeutic options. Emerging evidence highlights PANoptosis—a coordinated interplay of pyroptosis, apoptosis, and necroptosis—as a critical driver of metabolic and immune dysregulation in NAFLD. Here, we integrated multiple datasets and interpretable machine learning to unravel the role of PANoptosis in NAFLD diagnosis, subtyping, and immune microenvironment remodeling. By intersecting differentially expressed genes and PANoptosis-related genes, we identified 9 hub genes (e.g., TRADD, CASP6, TNFRSF1A and TNFAIP3) and constructed a robust diagnostic model (AUC = 0.976) validated via SHAP analysis and nomogram. Unsupervised consensus clustering stratified NAFLD patients into two PANoptosis-driven subtypes (C1/C2 and CA/CB), revealing distinct immune cell infiltration patterns and pathway activation. Single-cell sequencing further localized hub genes to immune cells and revealed their cell communication, implicating their roles in the progression of NAFLD. Molecular docking studies identified fostamatinib and minocycline as potential therapeutic candidates, while pan-cancer analysis revealed that TNFRSF1A overexpression is associated with poor prognosis across multiple cancer types. This study enhances the understanding of PANoptosis as a crucial diagnostic and therapeutic target in NAFLD, providing novel insights into immune-mediated pathogenesis and paving the way for treatment strategies. |
| format | Article |
| id | doaj-art-ed869549941d48c3b2b7f5ab4e6d40c9 |
| institution | Kabale University |
| issn | 0171-2985 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Immunobiology |
| spelling | doaj-art-ed869549941d48c3b2b7f5ab4e6d40c92025-08-20T03:26:09ZengElsevierImmunobiology0171-29852025-05-01230315290910.1016/j.imbio.2025.152909Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLDFeng Tian0Yuqi Zhao1Xinyang He2Yu Zhang3Minxuan Hu4Yiwei Liang5Ziyou Tian6Yaxian Gao7Yongwei Wang8Clinical College of Chengde Medical University, Chengde 067000,ChinaTraditional Chinese Medicine College of Chengde Medical University, Chengde 067000,ChinaNursing College of Chengde Medical University, Chengde 067000,ChinaNursing College of Chengde Medical University, Chengde 067000,ChinaClinical College of Chengde Medical University, Chengde 067000,ChinaNursing College of Chengde Medical University, Chengde 067000,ChinaBasic Medical College of Chengde Medical University, Chengde 067000,ChinaDepartment of Immunology, Basic Medical Institute, Chengde Medical University, Anyuan road, Shuangqiao district, Chengde 067000, Hebei, China; Corresponding authors.Department of Anatomy, Basic Medical Institute, Chengde Medical University, Anyuan road, Shuangqiao district, Chengde 067000, Hebei, China; Corresponding authors.Non-alcoholic fatty liver disease (NAFLD) is a global health challenge characterized by complex pathogenesis and limited therapeutic options. Emerging evidence highlights PANoptosis—a coordinated interplay of pyroptosis, apoptosis, and necroptosis—as a critical driver of metabolic and immune dysregulation in NAFLD. Here, we integrated multiple datasets and interpretable machine learning to unravel the role of PANoptosis in NAFLD diagnosis, subtyping, and immune microenvironment remodeling. By intersecting differentially expressed genes and PANoptosis-related genes, we identified 9 hub genes (e.g., TRADD, CASP6, TNFRSF1A and TNFAIP3) and constructed a robust diagnostic model (AUC = 0.976) validated via SHAP analysis and nomogram. Unsupervised consensus clustering stratified NAFLD patients into two PANoptosis-driven subtypes (C1/C2 and CA/CB), revealing distinct immune cell infiltration patterns and pathway activation. Single-cell sequencing further localized hub genes to immune cells and revealed their cell communication, implicating their roles in the progression of NAFLD. Molecular docking studies identified fostamatinib and minocycline as potential therapeutic candidates, while pan-cancer analysis revealed that TNFRSF1A overexpression is associated with poor prognosis across multiple cancer types. This study enhances the understanding of PANoptosis as a crucial diagnostic and therapeutic target in NAFLD, providing novel insights into immune-mediated pathogenesis and paving the way for treatment strategies.http://www.sciencedirect.com/science/article/pii/S0171298525000439Non-alcoholic fatty liver diseasePANoptosisSubtypesDiagnostic modelMolecular dockingSingle-cell sequencing |
| spellingShingle | Feng Tian Yuqi Zhao Xinyang He Yu Zhang Minxuan Hu Yiwei Liang Ziyou Tian Yaxian Gao Yongwei Wang Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLD Immunobiology Non-alcoholic fatty liver disease PANoptosis Subtypes Diagnostic model Molecular docking Single-cell sequencing |
| title | Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLD |
| title_full | Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLD |
| title_fullStr | Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLD |
| title_full_unstemmed | Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLD |
| title_short | Interpretable Machine Learning reveals the Role of PANoptosis in the Diagnosis and Subtyping of NAFLD |
| title_sort | interpretable machine learning reveals the role of panoptosis in the diagnosis and subtyping of nafld |
| topic | Non-alcoholic fatty liver disease PANoptosis Subtypes Diagnostic model Molecular docking Single-cell sequencing |
| url | http://www.sciencedirect.com/science/article/pii/S0171298525000439 |
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