Indoleamine 2,3-dioxygenase 1 mediated macrophage oxidative phosphorylation impairment drives pro-inflammatory M1 polarization aggravates acetaminophen-induced acute liver injury

  • Ecotoxicol Environ Saf. 2026 Jan 15:310:119774. doi: 10.1016/j.ecoenv.2026.119774.
Shanshan Kuang  1 ,  Yuhua Wang  2 ,  Caihua Feng  3 ,  Yawen Yuan  4 ,  Min Li  5 ,  Kaili Deng  6 ,  Weixing Zhong  7 ,  Jinjie Wen  8 ,  Chuying Zhou  9 ,  Qing Chen  10 ,  Shuwen Xie  11 ,  Sha Huang  12 ,  Zhiping Lv  13
Affiliations
  • 1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 2. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 3. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 4. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 5. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 6. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 7. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 8. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 9. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 10. Department of Pain Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: [email protected].
  • 11. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 12. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
  • 13. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
PMID: 41576503 DOI: 10.1016/j.ecoenv.2026.119774
Abstract

Acetaminophen (APAP)-induced acute liver injury (AILI) remains a predominant cause of acute liver failure worldwide, characterized by limited treatment options and a pressing need to elucidate underlying mechanisms for therapeutic development. While indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated as a potential target, its specific role and mechanistic action in AILI pathogenesis remain poorly understood. To elucidate the function and underlying mechanism of IDO1 during AILI, this study employed in vivo models with wild-type and IDO1-knockout mice, alongside in vitro co-culture systems with macrophages (RAW264.7 cells) and hepatocytes (AML-12 cells). The results revealed that macrophages adopted the pro-inflammatory M1 phenotype during early AILI, with significant IDO1 up-regulation. IDO1 deficiency significantly attenuated APAP-induced pro-inflammatory responses and oxidative stress. Mechanistically, APAP intoxication triggered IDO1 enrichment within macrophage mitochondria, where it inhibited Oxidative Phosphorylation (OXPHOS) and promoted a shift towards a pro-inflammatory M1 polarization; this metabolic reprogramming was abrogated by the mitochondrial-targeted antioxidant Mito-TEMPO. Furthermore, pharmacological inhibition of IDO1 suppressed the M1 phenotype in macrophages and mitigated subsequent hepatocyte damage in co-culture, whereas IDO1 overexpression amplified the injury. Our findings establish that IDO1 modulates macrophage immunometabolism to foster a pro-inflammatory intrahepatic milieu, thereby aggravating hepatocyte mitochondrial oxidative stress and death in early AILI. This reveals IDO1 as a key regulator of immune-metabolic crosstalk in AILI and underscores its potential both as a biomarker and a promising therapeutic target.

Keywords
Acetaminophen-induced acute liver injury (AILI); Indoleamine 2,3-dioxygenase 1 (IDO1); M1 polarization; Macrophages; Oxidative phosphorylation.
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