Targeting MYH9 by Usenamine A suppresses lung cancer via activation of the endoplasmic reticulum stress-autophagy axis.

Authors

Dongxiao Liu, Xuejiao Wei, Huiming Huang, Yingying Tian, Fei Wang, Zhuguo Wang, Xinyu Qiu, Ruoxin Zhang, Yufeng Gao, Wanying Xie, Xiaoxue Wang, Pengfei Tu, Changhai Qu, Zhongdong Hu

Published in

Biochemical pharmacology. Pages 118342. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

Lung cancer is one of the most common malignant tumors worldwide, posing a major risk to human health and survival. The identification of antitumor active compounds from natural products is a critical avenue for the development of anticancer drugs. Usenamine A (UA), a natural dibenzofuran compound extracted from Usnea longissima Ach. in our lab, has shown significant antitumor efficacy. However, the effect of UA against lung cancer and its specific mechanisms remain unclear. This study demonstrated that UA significantly inhibited lung cancer cell proliferation and induced apoptosis. Furthermore, UA induced endoplasmic reticulum (ER) expansion, markedly increased the levels of Ca²⁺, and significantly upregulated the expression of ER stress-related proteins, including HSPA5, p-PERK, p-eIF2α, ATF4, and CHOP, in these cells. Therefore, UA induced ER stress in lung cancer cells. Furthermore, UA-induced ER stress contributed to its lung cancer-suppressive activity. Additionally, UA-induced autophagy activation was implicated in its lung cancer-suppressive activity. The induction of ER stress activated autophagy in lung cancer cells. Moreover, the inhibition of ER stress considerably impaired the activation of autophagy induced by UA in lung cancer cells. Consequently, UA activated the ER stress-autophagy axis in lung cancer cells. In addition, myosin heavy chain 9 (MYH9) was identified as a target of UA in lung cancer cells, and MYH9 knockdown compromised UA-induced ER stress in these cells. In vivo, UA significantly inhibited tumor growth in a subcutaneous syngeneic Lewis lung carcinoma (LLC) model in C57BL/6J mice, achieving a tumor inhibition rate of 57.20%. Furthermore, UA induced ER stress and altered autophagy-related markers in LLC tumor tissues. In summary, UA exerted its lung cancer-suppressive activity by activating the PERK/eIF2α/ATF4/CHOP signaling cascade to drive the ER stress-autophagy axis and ultimately inducing apoptosis, with MYH9 acting as a crucial target of UA-induced ER stress in lung cancer cells. UA may serve as a promising lead compound for further development against lung cancer, while MYH9 emerged as a promising therapeutic target for lung cancer. This study offered a novel strategy for lung cancer treatment.

PMID:
42580489
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.

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