2. Academic Validation
  3. Galactomannan tetrasaccharide targets mannose receptor to suppress hepatocellular carcinoma growth through ROS/JNK signaling-induced apoptosis and ROS-mediated autophagy-dependent cell death

Galactomannan tetrasaccharide targets mannose receptor to suppress hepatocellular carcinoma growth through ROS/JNK signaling-induced apoptosis and ROS-mediated autophagy-dependent cell death

  • Bioorg Chem. 2025 Sep 19:165:109012. doi: 10.1016/j.bioorg.2025.109012.
Shuying Li 1,  Han Gao 2,  Jielin Zhao 2,  Guirong Wang 3,  Guofeng Gu 4
Affiliations

Affiliations

  • 1 National Glycoengineering Research Center and NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, 72 Binhai Road, Qingdao 266237, China; School of Pharmaceutical Sciences, Zhejiang Chinese Medicinal University, 260 Baichuan Road, Hangzhou 311400, China.
  • 2 National Glycoengineering Research Center and NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, 72 Binhai Road, Qingdao 266237, China.
  • 3 Department of Laboratory Medicine, Linyi Peoples' Hospital, Intersection of Wuhan Road and Wohushan Road, Linyi 276000, China. Electronic address: guirongwang2030@163.com.
  • 4 National Glycoengineering Research Center and NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, 72 Binhai Road, Qingdao 266237, China. Electronic address: guofenggu@sdu.edu.cn.
PMID: 40992041 DOI: 10.1016/j.bioorg.2025.109012
Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Studies have documented the antitumor activities of various Polysaccharides derived from Antrodia cinnamomea (AC); however, to date, the antitumor activity of the oligosaccharide fragment related to galactomannan polysaccharide in AC remains unreported. In this study, we disclosed that the backbone tetrasaccharide derivative of AC galactomannan, designated as ACP-3, demonstrates specific binding to mannose receptors (MR) on the surface of Hep G2 cells, facilitating its cellular internalization. This interaction thereby elicited potent antiproliferative effects through dual mechanisms: ROS/JNK signaling-induced Apoptosis and ROS-mediated autophagy-induced cell death. In vivo studies further validated the tumor-targeting capability of ACP-3, as monotherapy significantly suppresses the growth of H22 solid tumors. Notably, the co-administration of ACP-3 with cyclophosphamide (CTX) could synergistically enhance antitumor activity and concurrently alleviate CTX-induced adverse effects such as weight loss, hepatorenal toxicity, and immune dysfunction. These findings collectively establish ACP-3 as a promising therapeutic candidate for the treatment of HCC.

Keywords

Antitumor activity; Antrodia cinnamomea; Apoptosis; Autophagy; Galactomannan oligosaccharide; Mannose receptor.

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