Usenamine a potentiates anti-CRC activity of sorafenib by inducing autophagy and inhibiting YAP pathway through targeting SOD2 PMID: 41861687

ADC Targets in Oncology

2026-04-10

Usenamine a potentiates anti-CRC activity of sorafenib by inducing autophagy and inhibiting YAP pathway through targeting SOD2

Phytomedicine. 2026 Jun:155:158086. doi: 10.1016/j.phymed.2026.158086.

Weishan Zhuge ¹ , Jiayang Kuang ² , Keke Kuang ² , Meilin Rao ² , Dan Jian ² , Haizhen Lin ² , Zijun Li ³ , Shaotang Li ⁴ , Yihu Zheng ⁴ , Namki Cho ⁵ , Xiaokun Li ⁶ , Ri Cui ⁷

Affiliations

1. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
2. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
3. National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
4. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
5. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea. Electronic address: [email protected].
6. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].
7. Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: [email protected].

Abstract

Background: Colorectal Cancer (CRC) is among the most prevalent malignancies globally, with its incidence continuing to rise in recent years. Sorafenib, a multi-kinase inhibitor, has shown therapeutic effects in advanced CRC. Usenamine A (UD32-3), a natural compound, is isolated from lichens. However, anti-tumor activity of UD32-3 in CRC and its biological functions in anti-CRC activity of sorafenib remain unknown.

Purpose: This study aims to elucidate the mechanism underlying anti-CRC effects of UD32-3 and its potential to enhance the therapeutic efficacy of sorafenib.

Study design and methods: Immunofluorescence assays were employed to investigate Reactive Oxygen Species (ROS) and Autophagy levels. Gene knockdown or overexpression was performed using Lipofectamine 3000 reagent, and relative gene and protein expression levels were evaluated by quantitative Real-Time PCR (qRT-PCR) and Western blot analyses. Molecular docking analysis was performed to investigate the interaction between UD32-3 and superoxide dismutase 2 (SOD2). Mouse xenograft models were employed to evaluate the effects of combination therapy with UD32-3 and sorafenib.

Results: UD32-3 exerts anti-CRC activity by inducing ROS-mediated Autophagy and inhibiting YAP pathway through targeting SOD2. Knocking down SOD2 sufficiently induced ROS generation and Autophagy, and inhibited the YAP pathway, thereby enhancing the anti-CRC activity of UD32-3. Conversely, overexpression of SOD2 yielded opposite results, attenuating these effects. Combined treatment with UD32-3 and sorafenib exerted synergistic anti-tumor activities by activating Autophagy and inhibiting YAP signaling pathway. Additionally, YAP Inhibitor strengthened anti-CRC activity of UD32-3 and sorafenib by inhibiting SOD2 expression, suggesting autophagy-mediated negative feedback loop between SOD2 and YAP.

Conclusions: UD32-3 has significant druggable potential, and combination treatment of UD32-3 and sorafenib may serve as an effective therapeutic strategy for patients with certain CRC.

Keywords

Autophagy; CRC; SOD2; Sorafenib; Usenamine A.