2. Academic Validation
  3. HIF-1α drives pyroptosis in extravillous trophoblasts by suppressing PPAR-γ to activate the NLRP3 inflammasome in RA-complicated pregnancy

HIF-1α drives pyroptosis in extravillous trophoblasts by suppressing PPAR-γ to activate the NLRP3 inflammasome in RA-complicated pregnancy

  • Int Immunopharmacol. 2026 Jun 1:178:116522. doi: 10.1016/j.intimp.2026.116522.
Tianjing Zhang 1,  Yuchen Zhao 1,  Wenping He 1,  Yu Chen 1,  Qinyu Liu 1,  Yujing Tang 1,  Shuo Geng 1,  Li Xu 1,  Li Tao 2,  Zhen Yu 2,  Xianzheng Zhang 3,  Yuanyuan Yang 4,  Jiemin Zhao 5,  Lingling Zhang 6
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Hefei 230032, China.
  • 2 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
  • 3 Institute of Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Hefei 230032, China. Electronic address: [email protected].
  • 4 Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: [email protected].
  • 5 Institute of Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Hefei 230032, China. Electronic address: [email protected].
  • 6 Institute of Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Hefei 230032, China. Electronic address: [email protected].
PMID: 41886921 DOI: 10.1016/j.intimp.2026.116522
Abstract

Pregnancies in women with rheumatoid arthritis (RA) are at high risk of adverse outcomes, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that maternal inflammation in RA reprograms the maternal-fetal interface, leading to impaired spiral artery remodeling, which is a hallmark of placental dysfunction. Through integrated analysis of clinical samples, collagen-induced arthritis (CIA) mouse models, and in vitro cell models, we reveal that a sustained hypoxic placental microenvironment stabilizes hypoxia-inducible factor 1-alpha (HIF-1α) in RA pregnancies, thereby driving Pyroptosis in extravillous trophoblasts (EVTs) and defective spiral artery remodeling. HIF-1α suppresses Peroxisome Proliferator-activated Receptor gamma (PPAR-γ) expression. This disruption of the balance between PPAR-γ and NOD-like Receptor family pyrin domain containing 3 (NLRP3) relieves the inhibitory effect of PPAR-γ on NLRP3 inflammasome assembly, leading to Pyroptosis in EVTs. This pathway was validated in a HIF-1α haploinsufficient (HIF-1α+/-) CIA mouse model. Crucially, the placental pathology was significantly mitigated, with attenuated hypoxia, reduced pyroptotic signaling, restored spiral artery remodeling, and improved pregnancy outcomes in HIF-1α+/- CIA mice. Collectively, our findings define a novel HIF-1α-mediated Pyroptosis pathway in EVTs as a critical link between placental hypoxia and dysfunction in RA, providing a promising therapeutic target for improving maternal-fetal outcomes.

Keywords

Extravillous trophoblasts; HIF-1α; NLRP3; PPAR-γ; Pyroptosis; Rheumatoid arthritis.

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