慢性应激诱导的肾上腺素（EPI）会加速乳腺癌的进展和转移，但其分子机制仍不清楚。在此，我们发现乳腺癌患者的循环 EPI 水平与泛素特异性肽酶 22 (USP22) 的肿瘤表达之间存在很强的正相关性。 USP22 通过增强脂肪甘油三酯脂肪酶 (ATGL) 介导的脂肪分解来促进 EPI 诱导的乳腺癌进展和转移。靶向USP22缺失降低了ATGL表达和脂肪分解，随后抑制了EPI介导的乳腺癌肺转移。 USP22 充当 Atgl 基因转录因子 FOXO1 的真正去泛素酶，EPI 构建了一条脂肪分解信号通路，通过 AKT 介导的磷酸化来稳定 USP22。值得注意的是，USP22 磷酸化水平与乳腺癌中的 EPI 以及涉及 FOXO1 和 ATGL 的下游途径呈正相关。药理学 USP22 抑制与 β 受体阻滞剂在治疗临床前异种移植乳腺癌模型中具有协同作用。这项研究揭示了 EPI 促肿瘤作用背后的分子途径，并为将 USP22 抑制与 β 受体阻滞剂相结合治疗侵袭性乳腺癌提供了强有力的理论依据。

Chronic stress-induced epinephrine (EPI) accelerates breast cancer progression and metastasis, but the molecular mechanisms remain unclear. Herein, we found a strong positive correlation between circulating EPI levels and the tumoral expression of ubiquitin-specific peptidase 22 (USP22) in patients with breast cancer. USP22 facilitated EPI-induced breast cancer progression and metastasis by enhancing adipose triglyceride lipase (ATGL)-mediated lipolysis. Targeted USP22 deletion decreased ATGL expression and lipolysis, subsequently inhibiting EPI-mediated breast cancer lung metastasis. USP22 acts as a bona fide deubiquitinase for the Atgl gene transcription factor FOXO1, and EPI architects a lipolysis signaling pathway to stabilize USP22 through AKT-mediated phosphorylation. Notably, USP22 phosphorylation levels are positively associated with EPI and with downstream pathways involving both FOXO1 and ATGL in breast cancers. Pharmacological USP22 inhibition synergized with β-blockers in treating preclinical xenograft breast cancer models. This study reveals a molecular pathway behind EPI's tumor-promoting effects and provides a strong rationale for combining USP22 inhibition with β-blockers to treat aggressive breast cancer.