肝细胞主要通过分泌调节细胞增殖、代谢和细胞间通讯的蛋白质来发挥功能。在肝细胞癌（HCC）的发展过程中，肝细胞分泌的蛋白质组动态改变，既是肿瘤发生的后果，也是诱因，但这一过程中分泌蛋白质的全部作用范围尚不清楚。在这里，我们展示分泌的伪丝氨酸蛋白酶PRSS35在HCC中发挥肿瘤抑制剂的作用。机理上，我们证明活性PRSS35通过前蛋白转化酶的裂解而被加工。然后，活性PRSS35通过靶向串联赖氨酸（KK）识别基序的裂解抑制CXCL2的蛋白质水平。因此，CXCL2的降解减弱了肿瘤的中性粒细胞招募和中性粒细胞的外泌性陷阱形成，最终抑制了HCC的进展。这些发现扩展了我们对肝细胞分泌物在癌症发展中作用的理解，同时为PRRS35作为治疗靶点或诊断生物标志物的临床转化提供了基础。 © 2023.作者。

Hepatocytes function largely through the secretion of proteins that regulate cell proliferation, metabolism, and intercellular communications. During the progression of hepatocellular carcinoma (HCC), the hepatocyte secretome changes dynamically as both a consequence and a causative factor in tumorigenesis, although the full scope of secreted protein function in this process remains unclear. Here, we show that the secreted pseudo serine protease PRSS35 functions as a tumor suppressor in HCC. Mechanistically, we demonstrate that active PRSS35 is processed via cleavage by proprotein convertases. Active PRSS35 then suppresses protein levels of CXCL2 through targeted cleavage of tandem lysine (KK) recognition motif. Consequently, CXCL2 degradation attenuates neutrophil recruitment to tumors and formation of neutrophil extracellular traps, ultimately suppressing HCC progression. These findings expand our understanding of the hepatocyte secretome's role in cancer development while providing a basis for the clinical translation of PRRS35 as a therapeutic target or diagnostic biomarker.© 2023. The Author(s).