2. Academic Validation
  3. Luteolin mitigates inflammatory organ injury by targeting XIAP to block PANoptosis and mitochondrial dysfunction

Luteolin mitigates inflammatory organ injury by targeting XIAP to block PANoptosis and mitochondrial dysfunction

  • Int Immunopharmacol. 2026 Mar 15:173:116271. doi: 10.1016/j.intimp.2026.116271.
Fu-Li Shi 1,  Yang-Feng Lv 2,  Shi-Qi Luo 3,  Yu-Xuan Sun 4,  Xiang-Qiong Wen 2,  Yue-Xiang Ren 4,  Yu-Xing Yang 4,  Peng Yu 4,  Qiong-Feng Chen 5,  Xian-He Yang 4,  Shan Xu 4,  Jie Qing 4,  Dong-Yun Ouyang 3,  Jian-Ming Li 6
Affiliations

Affiliations

  • 1 Key Laboratory of Precision Pathology and Intelligent Diagnosis of Jiangxi Province, Department of Pathology and Molecular Pathology Institute, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Postdoctoral Research Station, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
  • 2 Key Laboratory of Precision Pathology and Intelligent Diagnosis of Jiangxi Province, Department of Pathology and Molecular Pathology Institute, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
  • 3 Department of Immunology and Microbiology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 4 Key Laboratory of Precision Pathology and Intelligent Diagnosis of Jiangxi Province, Department of Pathology and Molecular Pathology Institute, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
  • 5 Key Laboratory of Precision Pathology and Intelligent Diagnosis of Jiangxi Province, Department of Pathology and Molecular Pathology Institute, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Jiangxi Medical College, Nanchang University, Nanchang 330006, China; School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
  • 6 Key Laboratory of Precision Pathology and Intelligent Diagnosis of Jiangxi Province, Department of Pathology and Molecular Pathology Institute, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Pathology, Soochow University Medical School, Suzhou 215123, China. Electronic address: [email protected].
PMID: 41637826 DOI: 10.1016/j.intimp.2026.116271
Abstract

Introduction: PANoptosis, an inflammatory cell death pathway that integrates Pyroptosis, Apoptosis, and Necroptosis, contributes critically to the pathogenesis of inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). However, the molecular regulation of PANoptosis and its pharmacological intervention remain poorly defined.

Objectives: This study aimed to investigate the regulatory role of XIAP in PANoptosis and to evaluate the therapeutic potential of luteolin, a natural flavonoid, as a pharmacological inhibitor of PANoptosis.

Methods: Murine macrophage models were used to assess PANoptosis induction and inhibition. Structural and biochemical approaches were applied to determine the interaction between luteolin and XIAP. Mitochondrial function, ROS accumulation, oxidized mitochondrial DNA, and z-DNA generation were examined, while Autophagy was evaluated as a modulatory mechanism. Therapeutic efficacy was further validated in a poly(I:C)/LPS-induced HLH mouse model.

Results: XIAP was identified as an essential component of the PANoptosome complex, and its knockdown abolished PANoptosis formation. Luteolin directly bound to XIAP, destabilized its structure, and disrupted its interaction with PANoptosome, thereby blocking PANoptosome assembly. Luteolin preserved mitochondrial integrity, reduced ROS accumulation, and inhibited the generation of oxidized mtDNA and z-DNA. Importantly, luteolin enhanced autophagic clearance of damaged mitochondria by relieving XIAP-mediated suppression of Autophagy. In vivo, luteolin treatment significantly attenuated systemic inflammation, protected organ function, and improved survival in HLH mice, effects associated with diminished PANoptosome formation and reduced z-DNA accumulation.

Conclusions: This study establishes XIAP as a central regulator of PANoptosis and demonstrates luteolin as a natural inhibitor targeting XIAP to block PANoptosome assembly and mitochondrial dysfunction. These findings provide a novel pharmacological strategy for treating PANoptosis-driven inflammatory diseases.

Keywords

Hemophagocytic lymphohistiocytosis; Luteolin; PANoptosis; XIAP; mt-z-DNA.

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