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  3. Biliverdin alleviates cerebral ischemia-reperfusion injury by regulating the P4hb/MAPK/mTOR pathway to inhibit autophagy

Biliverdin alleviates cerebral ischemia-reperfusion injury by regulating the P4hb/MAPK/mTOR pathway to inhibit autophagy

  • Cell Signal. 2025 Aug:132:111815. doi: 10.1016/j.cellsig.2025.111815.
Huan Jiang 1,  Wenya Bai 1,  Yuan Yang 2,  Guilin Zhou 1,  Junjie Li 1,  Xuelian Li 1,  Xiaohong Wan 3,  Jianlin Shao 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China.
  • 2 Department of Anesthesiology, Second Affiliated Hospital of Kunming Medical University, 650000 Kunming, Yunnan Province, China.
  • 3 Department of Anesthesiology, Second Affiliated Hospital of Kunming Medical University, 650000 Kunming, Yunnan Province, China. Electronic address: 13888586162@163.com.
  • 4 Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 650032 Kunming, Yunnan Province, China. Electronic address: shaojianlin@kmmu.edu.cn.
PMID: 40258578 DOI: 10.1016/j.cellsig.2025.111815
Abstract

Background: Biliverdin (BV) exhibits anti-inflammatory and antioxidative effects. Autophagy activation is crucial in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). This study aimed to investigate whether BV could ameliorate CIRI by regulating Autophagy.

Methods: A middle cerebral artery occlusion-reperfusion (MCAO/R) model in Sprague-Dawley (SD) rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in PC12 cells were employed to explore the neuroprotective effects of BV and its underlying mechanisms. In these rats, once BV was administered post-MCAO/R, its treatment efficacy and underlying mechanisms were evaluated through behavioral, morphological, and molecular analyses. Alternatively, for PC12 cells, following successful OGD/R modeling, BV, Autophagy activator rapamycin, prolyl 4-hydroxylase beta (P4hb) knockdown or overexpression, and the specific inhibitors of three classic Autophagy pathways were applied. Cell viability (using CCK8 assay), Calcein/PI staining, autophagosome staining (using MDC assay), reverse transcription quantitative polymerase chain reaction, and western blot were subsequently carried out to investigate the mechanisms by which BV ameliorates CIRI.

Results: BV alleviated CIRI by inhibiting Autophagy. Further investigation suggested that BV downregulated P4hb expression. In vitro experiments showed that P4hb knockdown reduced Autophagy in post-CIRI cells, while its overexpression reversed the effects of BV. Rescue experiments indicated that MAPK pathway inhibitors counteracted the effects of P4hb overexpression on Autophagy post-CIRI.

Conclusion: BV improves CIRI by regulating the P4hb/MAPK/mTOR signaling pathway to inhibit Autophagy, offering a novel therapeutic strategy for ischemic stroke.

Keywords

Autophagy; Biliverdin; Cerebral ischemia-reperfusion injury; MAPK/mTOR signaling pathway; Oxygen-glucose deprivation/reoxygenation injury; Prolyl 4-hydroxylase beta.

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