Piroxicam accelerates diabetic foot ulcer healing via ERα-dependent mitochondrial protection and oxidative stress relief

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Introduction: The pathology of diabetic foot ulcer (DFU) is characterized by keratinocyte dysfunction, non-resolving inflammation, and oxidative stress. We aim to investigate the effects and mechanisms of piroxicam on DFU healing through regulating mitochondrial function and suppressing inflammation. Methods: DFU was established in male C57BL/6 J mice and ovariectomized female mice. Piroxicam (1% or 0.33%) solution or saline was then applied for 9 days. HaCaT cells were induced with high glucose (HG) and subsequently incubated with piroxicam (0, 1.2, 3.7, 11, 33, 100 nM). Results and Discussion: Piroxicam significantly promoted DFU healing and inhibited the fibrosis in male diabetic mice at a low dose. Consistently, piroxicam enhanced proliferation and migration, and inhibited inflammation, fibrosis, and cellular senescence in HG-induced HaCaT cells. Mechanistically, piroxicam alleviated HG-induced mitochondrial dysfunction by stabilizing the mitochondrial respiratory chain, increasing biogenesis, and enhancing mitophagy. These effects further attenuated oxidative stress and inhibited the cGAS-STING-NF-κB inflammatory pathway, thereby reducing the release of pro-inflammatory factors. Furthermore, molecular docking revealed that piroxicam bound to ERα, a finding further confirmed by a cellular thermal shift assay. HG induced a significant decrease in nuclear ERα protein levels, which was reversed by piroxicam, especially at 11 and 33 nM. Additionally, piroxicam's pro-healing and anti-inflammation effects were attenuated in ovariectomized female DFU mice. Piroxicam's protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen. In conclusion, piroxicam alleviates mitochondrial dysfunction and suppresses inflammatory responses by binding to ERα, which ultimately promotes DFU healing at low doses.

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