HSPA1B alleviates MEHP-induced developmental arrest of mouse preimplantation embryos by mediating ACSL4 ubiquitin degradation and suppressing lipid peroxidation.

Authors

Zihang Lin, Chengyu Lv, Bingping Wu, Xiuli Lian, Lvjing Luo, Dini Zhang, Xuanyi Wang, Yue Liu, Jiandong Sun, Shie Wang

Published in

The Journal of reproduction and development. Oct 24, 2026. Epub Oct 24, 2026.

Abstract

Lipid homeostasis is essential for the morula-to-blastocyst transition during mammalian preimplantation development, and excessive lipid peroxidation commonly induces developmental arrest at this stage. The heat shock protein HSPA1B participates in cellular proteostasis and lipid metabolism. However, its regulatory functions in early embryogenesis remain unclear. In the present study, knockdown of Hspa1b impaired blastocyst formation in mouse embryos. Proteomic screening suggested a physical interaction between HSPA1B and the lipid metabolic enzyme ACSL4, which was confirmed by co-immunoprecipitation and cytoplasmic co-localization analyses in morula-stage embryos. Hspa1b depletion did not alter Acsl4 transcription, but stabilized endogenous ACSL4 protein, resulting in lipid droplet accumulation, elevated intracellular ferrous ion levels, and increased lipid peroxidation. Concurrent knockdown of Hspa1b and Acsl4 rescued embryonic developmental defects and restored lipid homeostasis. Mechanistically, HSPA1B mediates K48-linked polyubiquitination and subsequent proteasomal degradation of ACSL4. Exposure to mono(2-ethylhexyl) phthalate (MEHP) triggered embryonic arrest, ACSL4 accumulation, and oxidative lipid damage, whereas Hspa1b overexpression ameliorated MEHP-associated embryonic toxicity. Overall, these results demonstrate that HSPA1B targets ACSL4 for K48 ubiquitination-dependent degradation to maintain lipid homeostasis required for blastocyst development. In addition, HSPA1B mitigated MEHP-induced injury in mouse preimplantation embryos by defining a regulatory axis for lipid metabolism and toxicant responses during early embryogenesis.

PMID:
42927920
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.

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