A recent study published in Engineering has shed light on the potential therapeutic effects of dihydrotanshinone I (DHT), a compound derived from the traditional Chinese herb Salvia miltiorrhiza, on ovarian cancer. The research, conducted by a team from Zhejiang Chinese Medical University and Jiangsu Normal University, reveals that DHT can induce autophagic cell death in ovarian cancer cells by disrupting the sortilin 1 (SORT1)-mediated autophagy–lysosome pathway.

Ovarian cancer is one of the deadliest malignancies affecting women, with the highest mortality rate among gynecological cancers. A distinguishing feature of ovarian cancer cells is their reduced autophagic flux compared to normal cells. This suggests that excessive autophagy activation or impaired autophagosome–lysosome fusion could lead to cancer cell death. The study investigated the effects of DHT on ovarian cancer cells, uncovering its mechanism of action through proteomic analysis and in vivo experiments.

The researchers found that DHT suppressed ovarian cancer growth by targeting SORT1, a protein involved in the autophagy–lysosome pathway. In vitro experiments demonstrated that DHT promoted the formation of autophagosomes, indicated by the increased expression of microtubule-associated protein 1 light chain 3-II (LC3-II), while inhibiting the fusion of autophagosomes with lysosomes. This disruption in the autophagic flux led to the accumulation of autophagosomes and ultimately induced autophagic cell death in ovarian cancer cells.

To validate these findings, the researchers utilized an orthotopic ovarian cancer model in mice. The results showed that DHT treatment significantly reduced tumor growth and weight, corroborating the in vitro observations. Additionally, DHT was found to decrease SORT1 expression in tumors, further supporting its role in disrupting the autophagy–lysosome pathway.

The study also explored the interaction between DHT and SORT1. Co-immunoprecipitation and cellular thermal shift assays revealed that DHT directly targeted SORT1, promoting its ubiquitin-dependent degradation. This degradation of SORT1 led to the release of autophagy-related proteins ATG5 and ATG16L1, which enhanced autophagosome formation and disrupted the autophagic flux.

SORT1, encoded by the SORT1 gene, is primarily located on the endoplasmic reticulum and lysosomal membranes, where it is involved in protein transport to lysosomes. Previous studies have shown that SORT1 mediates ovarian cancer progression by enhancing cell proliferation, migration, and invasion. High SORT1 expression has been detected in over 75% of clinical ovarian tumor samples, making it a promising therapeutic target.

The findings of this study highlight the potential of DHT as a novel therapeutic agent for ovarian cancer. By targeting SORT1 and disrupting the autophagy–lysosome pathway, DHT induces autophagic cell death, offering a new strategy for the treatment of this deadly disease. Future research may focus on further elucidating the underlying mechanisms and exploring the clinical applications of DHT in ovarian cancer therapy.

The paper “Dihydrotanshinone I Induces Autophagic Cell Death in Ovarian Cancer by Disrupting the SORT1-Mediated Autophagy–Lysosome Pathway,” is authored by Chengtao Sun, Shengqian Deng, Bing Han, Xiaoxiao Han, Yanan Yu, Man Li, Jiayi Lou, Chengping Wen, Jiong Wu, Guoyin Kai. Full text of the open access paper: https://doi.org/10.1016/j.eng.2025.06.020. For more information about Engineering, visit the website at https://www.sciencedirect.com/journal/engineering.