miR-15b-5p promotes HgCl 2 -induced chicken embryo kidney cells ferroptosis by targeting β-TrCP-mediated ATF4 ubiquitin degradation.

Mercuric chloride (HgCl ₂ ), a widespread environmental pollutant, induces ferroptosis in chicken embryonic kidney (CEK) cells. Whereas activating transcription factor 4 (ATF4), a critical mediator of oxidative homeostasis, plays a dual role in ferroptosis, but its precise mechanisms in HgCl ₂ -induced ferroptosis remain elusive. This study aims to investigate the function and molecular mechanism of ATF4 in HgCl ₂ -induced ferroptosis. Our results revealed that ATF4 was downregulated during HgCl ₂ -induced ferroptosis in CEK cells. Surprisingly, HgCl ₂ exposure has no significant impact on ATF4 mRNA level. Further investigation indicated that HgCl ₂ enhanced the expression of the E3 ligase beta-transducin repeat-containing protein (β-TrCP) and increased ATF4 ubiquitination. Subsequent findings identified that miR-15b-5p as an upstream modulator of β-TrCP, with miR-15b-5p downregulation observed in HgCl ₂ -exposed CEK cells. Importantly, miR-15b-5p mimics suppressed β-TrCP expression and reversed HgCl ₂ -induced cellular ferroptosis. Mechanistically, HgCl ₂ inhibited miR-15b-5p, and promoted β-TrCP-mediated ubiquitin degradation of ATF4, thereby inhibited the expression of antioxidant-related target genes and promoted ferroptosis. In conclusion, our study highlighted the crucial role of the miR-15b-5p/β-TrCP/ATF4 axis in HgCl ₂ -induced nephrotoxicity, offering a new therapeutic target for understanding the mechanism of HgCl ₂ nephrotoxicity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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