Poncirin Alleviates Hypoxic Pulmonary Hypertension by Blocking TDP43-Mediated Macrophage Pyroptosis

This study aimed to investigate the therapeutic effects of Poncirin on hypoxic pulmonary hypertension (HPH) and to elucidate the underlying mechanism, with a specific focus on transactive response DNA-binding protein 43 (TDP43)-mediated macrophage pyroptosis. A rat model of HPH was established using a hypobaric hypoxia chamber. In vitro, rat alveolar macrophages (NR8383 cells) and pulmonary artery smooth muscle cells (PASMCs) were cultured under normoxic or hypoxic (1% O₂) conditions. TDP43 expression was modulated through small interfering RNA (siRNA)-mediated knockdown or lentivirus-mediated overexpression. Poncirin was administered at a dose of 30 mg/kg in vivo and at a concentration of 50 μM in vitro to assess its pharmacologic effects. The results demonstrated that TDP43 expression was markedly upregulated in lung tissues of rats with HPH and in hypoxia-exposed NR8383 cells, and this was accompanied by increased macrophage accumulation around pulmonary arterioles. Hypoxia-induced TDP43 upregulation promoted macrophage pyroptosis via activation of NLRP3, Caspase 1, and N-GSDMD, leading to enhanced release of the inflammatory cytokine interleukin-1β (IL-1β), which in turn facilitated PASMCs proliferation. Poncirin significantly attenuated hypoxia-induced macrophage pyroptosis and PASMCs proliferation in both in vivo and in vitro models by downregulating TDP43 expression. Collectively, these findings identify TDP43 as a key mediator in the pathogenesis of HPH and support Poncirin as a potential therapeutic agent for HPH through targeting of TDP43-mediated macrophage pyroptosis.