Metformin antagonizes nickel-refining fumes-induced cell pyroptosis via Nrf2/GOLPH3 pathway in vitro and in vivo

Nickel compounds, an international carcinogen in the industrial environment, increased the risk of lung inflammation even lung cancer in Ni refinery workers. Metformin has displayed the intense anti-inflammation and anti-cancer properties through regulating pyroptosis. This study was designed to explore whether Nickel-refining fumes (NiRF) can induce cell pyroptosis and how AMPK/CREB/Nrf2 mediated the protection afforded by metformin against Ni particles-induced lung impairment. Our results represented that Ni fumes exposure evoked pyroptosis via GOLPH3 and induced oxidative stress, while, metformin treatment alleviated Ni particles-mediated above changes. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) involved in the protection of metformin, and the deficiency of Nrf2 attenuated the beneficial protection. We also determined that Nrf2 was a downstream molecule of AMPK/CREB pathway. Furthermore, male C57BL/6 mice were administered with Ni at a dose of 2 mg/kg by non-exposed endotracheal instillation and metformin (100, 200 and 300 mg/kg) via oral gavage for 4 weeks. The results indicated that NiRF promoted GOLPH3 and pyroptosis by stimulating NLRP3, caspase-1, N-GSDMD, IL-18 and IL-1β expression. However, various doses of metformin reduced GOLPH3 and the above protein levels of pyroptosis, also improved AMPK/CREB/Nrf2 expression. In summary, we found that metformin suppressed NiRF-connected GOLPH3-prompted pyroptosis via AMPK/CREB/Nrf2 signaling pathway to confer pulmonary protection.