---
title: "Ganoderma microsporum immunomodulatory protein (GMI) suppresses osteosarcoma via ROS, ER stress, a"
id: "pubmed-42035602"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42035602"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42035602/"
doi: "10.1016/j.bioorg.2026.109909"
published_at: "2026-08-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Ganoderma microsporum immunomodulatory protein (GMI) suppresses osteosarcoma via ROS, ER stress, a
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42035602
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42035602/)
- **DOI:** [10.1016/j.bioorg.2026.109909](https://doi.org/10.1016%2Fj.bioorg.2026.109909)
- **Published At:** 2026-08-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Osteosarcoma remains a chemoresistant aggressive bone cancer; the study evaluated a fungal-derived immunomodulatory protein, **GMI**, for anticancer effects. - GMI selectively decreased viability of human osteosarcoma cell lines **HOS** and **U2OS** while showing low toxicity to normal osteoblasts. - Cellular changes included morphological alterations, chromatin condensation, reduced colony formation, apoptosis, and **G2/M cell-cycle arrest**. - RNA sequencing revealed 292 upregulated and 158 downregulated genes, pointing to suppression of DNA repair, proliferation, cell-cycle progression, and mitochondrial pathways, with activation of autophagy-related signatures. - GMI increased intracellular **reactive oxygen species (ROS)**; the antioxidant **N-acetylcysteine (NAC)** reduced GMI-induced apoptosis and restored cell viability, implicating ROS in cytotoxicity. - GMI induced **endoplasmic reticulum (ER) stress** accompanied by sustained **JNK activation**, which shifted the balance of **BCL-2** family proteins (reduced anti-apoptotic BCL-2, increased pro-apoptotic members), promoting mitochondria-dependent apoptosis. - Autophagic responses were evident: increased acidic vesicular organelles, autophagosome-like structures, elevated **LC3B-II**, and decreased **p62** levels. - Pharmacologic inhibition of autophagy with **Bafilomycin A1 (Baf A1)**, **chloroquine (CQ)**, or **3-methyladenine (3-MA)** augmented GMI-induced apoptosis and further reduced viability, indicating autophagy plays a protective role. - In vivo, GMI significantly inhibited tumor growth in a xenograft model without affecting body weight, supporting translational potential. - Authors conclude GMI is a promising natural candidate for osteosarcoma therapy and recommend further preclinical and translational evaluation.
## Clinical Analysis & Structured Key Points
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Epub 2026 Apr 21. # Ganoderma Microsporum immunomodulatory protein suppresses osteosarcoma growth through redox imbalance and ER stress-driven apoptosis [Ying-Sui Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+YS&cauthor_id=42035602)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#full-view-affiliation-1 "School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan."), [Chi-Jen Chang](https://pubmed.ncbi.nlm.nih.gov/?term=Chang+CJ&cauthor_id=42035602)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#full-view-affiliation-2 "School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Division of Pediatric Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan."), [Tsung-Ming Chang](https://pubmed.ncbi.nlm.nih.gov/?term=Chang+TM&cauthor_id=42035602)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#full-view-affiliation-1 "School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan."), [Peng Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+P&cauthor_id=42035602)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#full-view-affiliation-3 "Liaison Center for Innovative Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan."), [Ju-Fang Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+JF&cauthor_id=42035602)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#full-view-affiliation-4 "School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan; Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan; Department of Medical Research, China Medical University, Hospital, China Medical University, Taichung 404328, Taiwan. Electronic address: jufangliu@tmu.edu.tw.") Affiliations Expand ### Affiliations * 1 School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan. * 2 School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Division of Pediatric Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan. * 3 Liaison Center for Innovative Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan. * 4 School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan; Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan; Department of Medical Research, China Medical University, Hospital, China Medical University, Taichung 404328, Taiwan. Electronic address: jufangliu@tmu.edu.tw. * PMID: **42035602** * DOI: [ 10.1016/j.bioorg.2026.109909 ](https://doi.org/10.1016/j.bioorg.2026.109909) Item in Clipboard # Ganoderma Microsporum immunomodulatory protein suppresses osteosarcoma growth through redox imbalance and ER stress-driven apoptosis Ying-Sui Sun et al. Bioorg Chem. 2026. Show details Display options Display options Format Abstract PubMed PMID Bioorg Chem Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bioorg+Chem%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Bioorg+Chem%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) . 2026 Aug 5:177:109909. doi: 10.1016/j.bioorg.2026.109909. Epub 2026 Apr 21. ### Authors [Ying-Sui Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+YS&cauthor_id=42035602)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#short-view-affiliation-1 "School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan."), [Chi-Jen Chang](https://pubmed.ncbi.nlm.nih.gov/?term=Chang+CJ&cauthor_id=42035602)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#short-view-affiliation-2 "School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Division of Pediatric Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan."), [Tsung-Ming Chang](https://pubmed.ncbi.nlm.nih.gov/?term=Chang+TM&cauthor_id=42035602)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#short-view-affiliation-1 "School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan."), [Peng Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+P&cauthor_id=42035602)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#short-view-affiliation-3 "Liaison Center for Innovative Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan."), [Ju-Fang Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+JF&cauthor_id=42035602)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42035602/#short-view-affiliation-4 "School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan; Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan; Department of Medical Research, China Medical University, Hospital, China Medical University, Taichung 404328, Taiwan. Electronic address: jufangliu@tmu.edu.tw.") ### Affiliations * 1 School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan. * 2 School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan; Division of Pediatric Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan. * 3 Liaison Center for Innovative Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Japan. * 4 School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 110301, Taiwan; Translational Medicine Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111045, Taiwan; Department of Medical Research, China Medical University, Hospital, China Medical University, Taichung 404328, Taiwan. Electronic address: jufangliu@tmu.edu.tw. * PMID: **42035602** * DOI: [ 10.1016/j.bioorg.2026.109909 ](https://doi.org/10.1016/j.bioorg.2026.109909) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Osteosarcoma (OS) is an aggressive bone malignancy with limited therapeutic advances and persistent chemoresistance, highlighting the need for safer and more effective treatments. Ganoderma microsporum immunomodulatory protein (GMI) is a fungal-derived bioactive molecule with reported antitumor activity, yet its effects in OS remain unknown. Here, we investigated the anticancer potential and mechanisms of GMI in osteosarcoma. GMI selectively reduced the viability of HOS and U2OS cells while exhibiting low toxicity toward normal osteoblasts. GMI induced morphological alterations, chromatin condensation, reduced colony formation, apoptosis, and G2/M arrest. RNA sequencing identified 292 upregulated and 158 downregulated genes, indicating suppression of DNA repair, proliferation, cell-cycle progression, and mitochondrial pathways, alongside activation of autophagy-related signatures. Mechanistically, GMI elevated intracellular reactive oxygen species (ROS), and N-acetylcysteine (NAC) attenuated GMI-induced apoptosis and restored viability. GMI-induced ER stress was associated with JNK activation, and sustained JNK activation disrupts the balance of BCL-2 family proteins by repressing anti-apoptotic BCL-2 and augmenting pro-apoptotic members, thereby driving mitochondria-dependent apoptosis in osteosarcoma cells. In addition, GMI treatment increases the formation of acidic vesicular organelles and autophagosome-like structures, accompanied by elevated LC3B-II and reduced p62 levels. Pharmacological blockade of autophagy using Baf A1, CQ, or 3-MA further augments GMI-induced apoptosis and exacerbates the reduction in cell viability. Finally, GMI significantly inhibited tumor growth in a xenograft model without affecting body weight. These findings identify GMI as a promising natural therapeutic candidate for osteosarcoma and warrants further preclinical and translational evaluation. **Keywords:** Apoptosis; Endoplasmic reticulum stress; Ganoderma microsporum immunomodulatory protein; Osteosarcoma; Reactive oxygen species. Copyright © 2026. Published by Elsevier Inc. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma. ](https://pubmed.ncbi.nlm.nih.gov/30704503/) Wang Z, Yin F, Xu J, Zhang T, Wang G, Mao M, Wang Z, Sun W, Han J, Yang M, Jiang Y, Hua Y, Cai Z.Wang Z, et al.J Exp Clin Cancer Res. 2019 Jan 31;38(1):44. doi: 10.1186/s13046-019-1047-9.J Exp Clin Cancer Res. 2019.PMID: 30704503Free PMC article. * [ Naringenin Induces ROS-Mediated ER Stress, Autophagy, and Apoptosis in Human Osteosarcoma Cell Lines. ](https://pubmed.ncbi.nlm.nih.gov/35056691/) Lee CW, Huang CC, Chi MC, Lee KH, Peng KT, Fang ML, Chiang YC, Liu JF.Lee CW, et al.Molecules. 2022 Jan 7;27(2):373. doi: 10.3390/molecules27020373.Molecules. 2022.PMID: 35056691Free PMC article. * [ GMI, an immunomodulatory protein from Ganoderma microsporum, induces autophagy in non-small cell lung cancer cells. ](https://pubmed.ncbi.nlm.nih.gov/21490426/) Hsin IL, Ou CC, Wu TC, Jan MS, Wu MF, Chiu LY, Lue KH, Ko JL.Hsin IL, et al.Autophagy. 2011 Aug;7(8):873-82. doi: 10.4161/auto.7.8.15698. Epub 2011 Aug 1.Autophagy. 2011.PMID: 21490426 * [ Acacetin Induces Apoptosis in Human Osteosarcoma Cells by Modulation of ROS/JNK Activation. ](https://pubmed.ncbi.nlm.nih.gov/33239866/) Wang S, Lin B, Liu W, Wei G, Li Z, Yu N, Xue X, Ji G.Wang S, et al.Drug Des Devel Ther. 2020 Nov 18;14:5077-5085. doi: 10.2147/DDDT.S275148. eCollection 2020.Drug Des Devel Ther. 2020.PMID: 33239866Free PMC article. * [ β-Elemonic acid inhibits the growth of human Osteosarcoma through endoplasmic reticulum (ER) stress-mediated PERK/eIF2α/ATF4/CHOP activation and Wnt/β-catenin signal suppression. ](https://pubmed.ncbi.nlm.nih.gov/32113150/) Zhao A, Zhang Z, Zhou Y, Li X, Li X, Ma B, Zhang Q.Zhao A, et al.Phytomedicine. 2020 Apr;69:153183. doi: 10.1016/j.phymed.2020.153183. Epub 2020 Feb 7.Phytomedicine. 2020.PMID: 32113150 [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42035602) ## MeSH terms * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Antineoplastic Agents* / chemistry Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Antineoplastic+Agents%2Fchemistry%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Antineoplastic+Agents) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Antineoplastic Agents* / isolation & purification Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Antineoplastic+Agents%2Fisolation+and+purification%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Antineoplastic+Agents) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Antineoplastic Agents* / pharmacology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Antineoplastic+Agents%2Fpharmacology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Antineoplastic+Agents) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Apoptosis* / drug effects Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Apoptosis%2Fdrug+effects%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Apoptosis) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Bone Neoplasms* / drug therapy Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bone+Neoplasms%2Fdrug+therapy%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Bone+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Bone Neoplasms* / metabolism Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bone+Neoplasms%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Bone+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Bone Neoplasms* / pathology Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Bone+Neoplasms%2Fpathology%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Bone+Neoplasms) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42035602/) * Cell Proliferation / drug effects Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Cell+Proliferation%2Fdrug+effects%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Cell+Proliferation) * [ Add to Search ](https:/
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