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Silkworm pupa protects against hypoxic lung injury by activating the Nrf2 pathway and inhibiting ferroptosis
Ying Ji1, Taian Jin2, Yumei Yan3
1College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China; Hangzhou Institute of Medicine Chinese Academy of Sciences, Hangzhou 310022, China.
Background:
Hypoxic lung injury (HLI) remains a significant clinical challenge, primarily characterized by oxidative damage and vascular remodeling. Recent studies have identified ferroptosis as a key contributor to hypoxia-related organ injury, and its inhibition represents a potential therapeutic strategy for HLI. Silkworm pupa (SW) contains diverse bioactive compounds with well-established anti-inflammatory, antioxidant, and anti-apoptotic properties. However, whether SW exerts protective effects against hypoxic lung injury through the regulation of ferroptosis remains unknown.
Methods:
In this study, a murine model of hypoxia was established, and two different doses of SW powder were administered via gavage. Cellular experiments were also conducted to evaluate the effects of SW on cell proliferation, antioxidant capacity, and metabolic and transcriptional reprogramming under hypoxic conditions, as well as to investigate the underlying molecular mechanisms.
Results:
SW treatment improved lung function and grip strength, reduced HIF-1α levels, alleviated pulmonary edema, and significantly decreased oxidative stress and lipid peroxidation in hypoxic mice. Cellular experiments further demonstrated that SW promoted cell proliferation under hypoxia, enhanced cellular antioxidant capacity, and induced substantial metabolic and transcriptional reprogramming. Mechanistic investigations revealed that SW upregulated the expression of p62, which competitively bound to Keap1, thereby disrupting the Keap1-Nrf2 interaction and leading to the release and subsequent nuclear translocation of Nrf2. The activated nuclear Nrf2 further promoted the expression of its downstream target genes, including xCT, FTH1, and NQO1, as well as enhancing glutathione (GSH) levels. These coordinated events collectively attenuated oxidative stress and ultimately inhibited hypoxia-induced ferroptosis.The use of ferroptosis regulators further confirmed the involvement of ferroptosis in lung injury.
Conclusion:
SW protects against HLI primarily by activating the Nrf2-mediated antioxidant response pathway and subsequently suppressing ferroptosis.
