Fahrul Nurkolis, Fan Maitri Aldian, Ricky Indra Alfaray, Abu Rizal Dwikatmono Johan, Andri Frediansyah, Happy Kurnia Permatasari, Nurpudji Astuti Taslim, Raymond Rubianto Tjandrawinata, Arifa Mustika, Bonglee Kim, Antonello Santini, Muhammad Miftahussurur
Gastric cancer remains a major global health burden with limited therapeutic options due to resistance and toxicity of current treatments. Marine red algae—Gracilaria edulis, Eucheuma denticulatum, and Kappaphycus striatus—are underexplored sources of bioactive compounds that may offer multi-targeted, low-toxicity agents for gastric cancer therapy. This study integrated phytochemical profiling, structure–activity relationship (SAR) analysis, network pharmacology, molecular docking, molecular dynamics simulations, and in vitro validation. SAR and docking analyses showed strong affinities of key compounds, including camptothecin and 24(S),25-epoxycholesterol, with gastric cancer targets (PTGER3, TGFBR1, IGF1R, CDK6, BRD4). Molecular dynamics confirmed the stability of camptothecin–TGFBR1 interactions. Kappaphycus striatus extract (KSE) significantly downregulated TGF-β1 expression in MKN-45 cells in a dose-dependent manner. Cytotoxicity assays demonstrated that KSE, camptothecin, and 24(S),25-epoxycholesterol selectively inhibited AGS and MKN-45 gastric cancer cells while sparing normal epithelial cells. The findings highlight Indonesian red algae as promising, safe, and sustainable sources of multi-targeted anti-gastric cancer agents. In particular, KSE and its bioactive constituents exhibit both cytotoxic and epigenetic modulatory effects, underscoring their potential for future therapeutic development. © 2025 Wiley-VCH GmbH.
Master of Basic Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; State Islamic University of Sunan Kalijaga (UIN Sunan Kalijaga), Yogyakarta, Indonesia; Medical Research Center of Indonesia, Surabaya, Indonesia; Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Oita, Japan; Helicobacter Pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia; Research Center for Food Technology and Processing (PRTPP), National Research and Innovation Agency (BRIN), Yogyakarta, Indonesia; Department of Biochemistry and Biomolecular, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia; Division of Clinical Nutrition, Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia; Center For Pharmaceutical and Nutraceutical Research and Policy, Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, Jakarta, Indonesia; Department of Anatomy, Histology, and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, South Korea; Department of Pharmacy, University of Napoli Federico II, Napoli, Italy; Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine—Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, Indonesia
