2. Academic Validation
  3. The neuronal ALAS2/5-ala axis mitigates chemotherapy-induced neurotoxicity via the BACH1/NRF2 pathway

The neuronal ALAS2/5-ala axis mitigates chemotherapy-induced neurotoxicity via the BACH1/NRF2 pathway

  • Br J Pharmacol. 2026 Jun;183(11):2695-2719. doi: 10.1111/bph.70358.
Wen-Yuan Zhang 1 2,  Qian-Qian Wei 1 2,  Tao Zhang 3 4,  Chunmei Geng 5,  Hai-Yan Wu 6,  Chang-Shui Wang 7,  Jing Chen 8 9,  Lei Feng 10,  Pei Jiang 3 4
Affiliations

Affiliations

  • 1 Department of Pharmacy, Zhongshan City People's Hospital, Zhongshan, China.
  • 2 School of Pharmaceutical Sciences, Zunyi Medical University, Zunyi, China.
  • 3 Translational Pharmaceutical Laboratory, Jining No.1 People's Hospital, Shandong First Medical University, Jining, China.
  • 4 Shandong Provincial Key Medical and Health Laboratory of Neuroinjury and Repair, Jining No.1 People's Hospital, Jining, China.
  • 5 Department of Pharmacy, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China.
  • 6 Zhongshan Psychological Society, Academic Committee, Zhongshan, China.
  • 7 Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China.
  • 8 Neurobiology Key Laboratory, Jining Medical University, Jining, China.
  • 9 Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
  • 10 Department of Neurosurgery, Jining First People's Hospital, Shandong First Medical University, Jining, China.
PMID: 41652971 DOI: 10.1111/bph.70358
Abstract

Background and purpose: Despite breakthroughs in immunotherapy and targeted therapies, chemotherapy remains indispensable in oncology.

Experimental approach: This study seeks to pinpoint key pathways in doxorubicin (DOX)-treated mouse hippocampus, utilising comprehensive transcriptomic and metabolomic analyses, and validating the mechanisms in vitro and in vivo.

Key results: Our multi-omics investigation revealed that sustained DOX exposure induced significant down-regulation of 5-aminolevulinate synthase 2 (ALAS2) and its catalytic product 5-aminolevulinic acid (5-ALA) in the hippocampal region. ALAS2 deficiency was specific to hippocampal neurons, which were more sensitive to oxidative damage than astrocytes or microglia. In vivo and in vitro studies demonstrated that 5-ALA administration or ALAS2 overexpression protected the brain from DOX-induced neurotoxicity. ALAS2 catalyses the condensation of glycine and succinyl-CoA to form 5-ALA, the key precursor of haem. Beyond its role in erythropoiesis, haem is a metabolite that modulates cellular redox homeostasis through interactions with the BACH1 (BTB and CNC homology 1)/NRF2 (nuclear factor erythroid 2 like 2) pathway. We found that DOX suppressed the ALAS2/5-ALA axis, thereby enhancing BACH1 stability. This stabilised BACH1 competes with NRF2 for binding to antioxidant response elements (AREs) in target gene promoters. Conversely, reinforcing the ALAS2/5-ALA axis elevated intracellular haem levels, promoting BACH1 degradation and enhancing NRF2 activity. Using a zebrafish model, we further highlighted the antioxidant and neuroprotective role of 5-ALA against DOX-induced neurotoxicity.

Conclusions and implications: In conclusion, this study elucidates a novel endogenous neuroprotective mechanism wherein the ALAS2/5-ALA axis modulates the BACH1/NRF2 pathway. 5-ALA shows promise for repurposing to mitigate chemotherapy-associated neurotoxicity.

Keywords

ALAS2/5‐ALA axis; BACH1/NRF2 pathway; doxorubicin; neurotoxicity; oxidative stress.

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