SIRT7 safeguards ERα proteostasis via deacetylation-dependent degradation of unliganded and misfolded receptors.

SIRT7 has been implicated in diverse physiological and pathological processes, yet its role in sexual dimorphism and the underlying molecular mechanisms remains insufficiently explored. Given that ERα-mediated estrogen signaling is a central regulator of sexual dimorphism and that ERα undergoes stringent quality control to preserve signaling sensitivity, we investigated whether SIRT7 and ERα are mechanistically connected. Here, we identify SIRT7 as a molecular inspector that safeguards the quality of estrogen receptor α (ERα) to fine-tune estrogen signaling through the regulation of ERα proteostasis. Under estrogen-deprived conditions or in the presence of misfolded ERα, SIRT7 deacetylates ERα and promotes its degradation through the E3 ubiquitin ligase STUB1, thereby maintaining a functional receptor pool and preserving estrogen responsiveness. During this process, deacetylated ERα competes with SIRT7 for STUB1 binding, an E3 ligase that is also required for SIRT7 protein turnover, thus leading to SIRT7 stabilization. As a feedback mechanism, upon estrogen (E2) stimulation, E2-bound ERα activates non-genomic MAPK signaling to trigger SIRT7 degradation via another E3 ligase UBR5, which ensures the proper receptor signaling activation. Given the central role of ERα in aging and hormone-related cancers, our findings highlight SIRT7 as a key regulator linking age-associated disorders and hormone-driven tumorigenesis.