Melittin-induced membrane disruption in hepatocellular carcinoma involves mtROS/GSDME-mediated pyroptosis
- 1Fujian Agriculture and Forestry University
Abstract
Although melittin is classically regarded as a membrane-lytic peptide, it remains unclear whether its membrane-disruptive effects in tumour cells result exclusively from direct peptide-lipid interactions or are partly generated by pyroptosis. Here, we show that melittin markedly suppresses the viability and clonogenic growth of human Huh7 and murine Hepa1-6 HCC cells and rapidly induces characteristic features of pyroptosis, including cell swelling, balloon-like membrane protrusions, plasma-membrane permeabilization and lactate dehydrogenase release. In Hepa1-6 cells, melittin induced prominent GSDME cleavage and accumulation of its pore-forming N-terminal fragment, whereas GSDMD activation was not detected. Quantitative proteomics and ultrastructural analyses further revealed pronounced mitochondrial perturbation after melittin treatment, accompanied by loss of mitochondrial membrane potential and increased mitochondrial reactive oxygen species (mtROS). Importantly, scavenging mitochondrial oxidants with Mito-TEMPO markedly reduced mtROS accumulation, attenuated pyroptotic membrane damage and partially restored cell viability. Collectively, our findings provide, to our knowledge, the first evidence that melittin induces pyroptotic cell death in HCC cells through a mechanism involving mitochondrial oxidative stress and GSDME processing. These results extend the conventional view of melittin as a direct membrane-lytic peptide and uncover an mtROS/GSDME-associated pyroptotic mechanism underlying its antitumour activity in HCC.
Related
- MYC-SNHG7-miR-34a-5p Feedback Loop Orchestrates GSDMD-Dependent Pyroptosis in Hepatocellular Carcinoma.
- Identification of hepatitis B virus-associated membrane proteins as prognostic biomarkers for hepatocellular carcinoma based on retrospective analysis of integrated membrane proteomics
- Graph attention network‐driven single‐cell omics analysis reveals how B4GALNT1‐mediated glycosylation remodelling of the ferroptosis–pyroptosis network promotes drug resistance in hepatocellular carcinoma
- Helicobacter pylori-Derived Outer Membrane Vesicles Promote Hepatocellular Carcinoma Cell Proliferation with PI3K/AKT/mTOR Activation and Cyclin D1 Upregulation
- Disruption of sphingolipid metabolism promotes tau seeding through endolysosomal membrane rigidification and rupture
BibTeX
@misc{zang2026melittininduced,
title = {{Melittin-induced membrane disruption in hepatocellular carcinoma involves mtROS/GSDME-mediated pyroptosis}},
author = {H. Zang and M. Lu and N. Fan and Y. Yang and J. Qiu and D. Chen and R. Guo},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.05.749568},
url = {https://www.biorxiv.org/content/10.64898/2026.09.05.749568v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Melittin-induced membrane disruption in hepatocellular carcinoma involves mtROS/GSDME-mediated pyroptosis
AU - H. Zang
AU - M. Lu
AU - N. Fan
AU - Y. Yang
AU - J. Qiu
AU - D. Chen
AU - R. Guo
PY - 2026
DA - 2026/09/05
PB - bioRxiv
DO - 10.64898/2026.09.05.749568
UR - https://www.biorxiv.org/content/10.64898/2026.09.05.749568v1
AB - Although melittin is classically regarded as a membrane-lytic peptide, it remains unclear whether its membrane-disruptive effects in tumour cells result exclusively from direct peptide-lipid interactions or are partly generated by pyroptosis. Here, we show that melittin markedly suppresses the viability and clonogenic growth of human Huh7 and murine Hepa1-6 HCC cells and rapidly induces characteristic features of pyroptosis, including cell swelling, balloon-like membrane protrusions, plasma-membrane permeabilization and lactate dehydrogenase release. In Hepa1-6 cells, melittin induced prominent GSDME cleavage and accumulation of its pore-forming N-terminal fragment, whereas GSDMD activation was not detected. Quantitative proteomics and ultrastructural analyses further revealed pronounced mitochondrial perturbation after melittin treatment, accompanied by loss of mitochondrial membrane potential and increased mitochondrial reactive oxygen species (mtROS). Importantly, scavenging mitochondrial oxidants with Mito-TEMPO markedly reduced mtROS accumulation, attenuated pyroptotic membrane damage and partially restored cell viability. Collectively, our findings provide, to our knowledge, the first evidence that melittin induces pyroptotic cell death in HCC cells through a mechanism involving mitochondrial oxidative stress and GSDME processing. These results extend the conventional view of melittin as a direct membrane-lytic peptide and uncover an mtROS/GSDME-associated pyroptotic mechanism underlying its antitumour activity in HCC.
ER -