E4BP4 interacts with PERK to form a feedback loop mediating cold-induced female reproductive disorders

In our previous report, PERK/NRF2/CX43/StAR/progesterone pathway activation in ovarian granulosa cells was shown to mediate cold-induced female reproductive disorders. However, how PERK is activated by low temperature remained unclear. In the present study, we found that the circadian protein E4BP4 was significantly upregulated in ovarian granulosa cells following exposure to cold or isoproterenol (ISO), a non-selective β-adrenergic receptor agonist that pharmacologically activates β-adrenergic signaling, a key component of the cold stress response. Mechanistically, E4BP4 interacted with PERK and was required for PERK activation and subsequent NRF2/CX43/StAR signaling, leading to increased progesterone secretion. Interestingly, NRF2 also acted as a transcriptional activator of E4BP4 under ISO treatment, and blocking PERK or NRF2 expression attenuated ISO-induced E4BP4 accumulation, suggesting a positive feedback loop involving PERK/NRF2/E4BP4. Collectively, these findings identify E4BP4 as a cold-responsive circadian protein that interacts with PERK and may contribute to cold-induced reproductive disorders via a bidirectional E4BP4-PERK feedback loop.