尽管在了解结直肠癌 (CRC) 发病机制方面取得了进展，但仍然存在显着差距，凸显了更深入见解的必要性。蛋白质稳态失调，包括表皮生长因子受体 (EGFR) 通路的扰动，仍然是结直肠癌发病机制的一个焦点。在此背景下，泛素连接酶和去泛素酶的作用引起了人们的关注，但对其精确贡献的探索仍处于早期阶段。为了解决这一问题，我们研究了去泛素酶 USP10 在 CRC 中的作用。我们的体外和体内研究揭示了 CRC 生物学的新范例，并揭示了新的机制轴，首次证明肌醇多磷酸 4-磷酸酶 II B 型 (INPP4B) 参与 USP10 介导的 CRC 调节。具体来说，我们的研究表明，USP10 的缺失会导致对 EGFR 酪氨酸激酶抑制剂吉非替尼和奥希替尼的敏感性降低。这伴随着 EGF 刺激后 AKT1/PKB 通路激活的减少，这是由 INPP4B 介导的。重要的是，体内异种移植实验验证了这些发现，并强调了 USP10（特别是与 INPP4B 结合）在驱动 CRC 进展中的关键作用。这些发现增强了我们对 CRC 病理学的理解，并揭示了 CRC 进展中涉及 USP10 和 INPP4B 的新调控轴。这一独特的见解将 USP10 和 INPP4B 确定为 CRC 的潜在治疗靶点。© 2024。作者。

Although there have been advances in understanding colorectal cancer (CRC) pathogenesis, significant gaps still exist, highlighting the need for deeper insights. Dysregulated protein homeostasis, including perturbations in the epidermal growth factor receptor (EGFR) pathway, remains a focal point in CRC pathogenesis. Within this context, the roles of ubiquitin ligases and deubiquitinases have attracted attention, but exploration of their precise contributions is still in its early stages. To address this gap, we investigated the involvement of the deubiquitinase USP10 in CRC. Our in vitro and in vivo study reveals a new paradigm in CRC biology and unravels a novel mechanistic axis, demonstrating for the first time the involvement of inositol polyphosphate 4-phosphatase type II B (INPP4B) in USP10-mediated CRC modulation. Specifically, our study demonstrates that the loss of USP10 results in reduced sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and osimertinib. This is accompanied by a decrease in the activation of the AKT1/PKB pathway upon EGF stimulation, which is mediated by INPP4B. Importantly, in vivo xenograft experiments validate these findings and highlight the crucial role of USP10, particularly in conjunction with INPP4B, in driving CRC progression. The findings enhance our understanding of CRC pathobiology and reveal a new regulatory axis involving USP10 and INPP4B in CRC progression. This unique insight identifies USP10 and INPP4B as potential therapeutic targets in CRC.© 2024. The Author(s).