Cigarette smoke disrupts osteogenic-adipogenic balance via Nrf2/HERC2 axis-driven ferroptosis

  • Free Radic Biol Med. 2025 Sep 10:S0891-5849(25)00971-2. doi: 10.1016/j.freeradbiomed.2025.09.014.
Wenjing Li  1 ,  Li Song  1 ,  Fanxuan Zhang  1 ,  Yuqin Pan  2 ,  Weixing Xu  3 ,  Feihua Huang  4 ,  Nani Wang  5
Affiliations
  • 1. Tongde Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
  • 2. College of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China.
  • 3. Tongde Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China. Electronic address: [email protected].
  • 4. Tongde Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China; College of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. Electronic address: [email protected].
  • 5. Tongde Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China; College of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, 311121, China. Electronic address: [email protected].
PMID: 40939850 DOI: 10.1016/j.freeradbiomed.2025.09.014
Abstract

Background: Disruption of iron homeostasis induced by cigarette smoke (CS) exposure is a major risk factor for smoking-related osteoporosis. However, the specific mechanisms remain unclear.

Methods: For in vivo experiments, wild-type (WT) and Nuclear factor E2-related factor 2 (Nrf2)-knockout mice received daily intraperitoneal injections of fresh CS extract for 60 days (0.2mL/20g/d), after which bone tissues were harvested for analysis of bone mineral density, histomorphometry, and molecular markers. In vitro experiments were performed using bone marrow-derived mesenchymal stem cells (BMSCs) exposed to CS, with or without treatment of the Nrf2 agonist CDDO. The changes of Nrf2/HECT and RLD domain containing E3 ubiquitin protein Ligase 2 (HERC2) pathway in both in vivo and in vitro models were evaluated.

Results: CS triggered Ferroptosis in murine bone and BMSCs by stimulating nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. This process shifted BMSCs differentiation towards adipogenesis via enhancing peroxisome proliferator-activated receptor-γ, while suppressing osteogenesis by inhibiting β-catenin. Mechanistically, CS upregulated Kelch-like ECH-associated protein 1, inhibiting Nrf2 nuclear translocation. Consequently, suppressed Nrf2 reduced transcription of downstream HERC2, impairing its role in degrading NCOA4 and ultimately activating ferroautophagy. Nrf2-knockout mice exhibited exacerbated CS-induced reduction in bone mineral density loss and decreased BMSCs markers. Similarly, Nrf2 or HERC2 knockdown in BMSCs amplified CS-induced Ferroptosis and adipogenic commitment. Conversely, Nrf2 activation via agonist bardoxolone restored HERC2 expression, thereby attenuating ferroautophagy and rebalancing osteogenic-adipogenic differentiation.

Conclusion: CS induces bone loss by dysregulating the Nrf2/HERC2 axis, leading to ferroautophagy-driven Ferroptosis and impaired osteogenesis. Pharmaceutical Nrf2 activation mitigates these effects, highlighting a novel therapeutic target for smoking-related osteoporosis.

Keywords
Bone marrow mesenchymal stem cells; Cigarette smoke; Ferritinophagy; Osteoporosis.
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