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N6-methyladenosine–modified circSLTM inhibits gastric cancer cell proliferation and promotes ferroptosis via interaction with HSPA8

ABSTRACT:

Circular RNAs (circRNAs) are dysregulated in cancers, with N6-methyladenosine (m⁶A)-modified species acting as key regulators of ferroptosis via iron metabolism and lipid peroxidation. This study examines the role of circSLTM (circ-0000605) in gastric cancer (GC). Clinical analyses of GEO data and 73 paired samples showed significant downregulation of circSLTM in GC, correlating with tumor differentiation and Lauren classification. Overexpression of circSLTM altered cellular metabolism and enhanced lipid peroxidation. When exposed to the ferroptosis inducer RSL3, cells overexpressing circSLTM exhibited elevated ROS and MDA, reduced GSH, downregulation of GPX4, SLC7A11, and FTH1, mitochondrial damage, and increased cell death. Knockdown of circSLTM reversed these phenotypes. Mechanistically, the m⁶A demethylase FTO destabilizes circSLTM, while circSLTM binds directly to the protein HSPA8, promoting its degradation via the ubiquitin-proteasome pathway. In vivo, the circSLTM–HSPA8 axis suppressed tumor growth by promoting ferroptosis. These findings identify circSLTM as a tumor suppressor in GC, acting through HSPA8 degradation to amplify ferroptotic signaling, and highlight its potential as a therapeutic target.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13702 | MetaboLights | 2026-01-16

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13702_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13702_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13702_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13702_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Purpose: Gastric cancer remains one of the deadliest neoplasms worldwide, with a high need for new therapeutic options. Efficacies of targeted therapies are often limited owing to the inter- and intratumoral heterogeneity of gastric cancer. Thus, drugs with broader mechanisms of action rather than relying on the inhibition of a single specific oncogene are needed. Preclinical studies have identified histone deacetylases (HDAC) and their respective isoforms as potential therapeutic targets in gastric cancer. However, clinical efficacies are moderate and the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. Methods: In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured using flow cytometry. Proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA (RT-qPCR) and protein level (Western Blot). Results: Upon HDACi treatment, lipid peroxidation levels were found increased in all tested cell lines. Class-I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Alterations of POR and SLC7A11 levels upon treatment were also confirmed in primary human gastric cancer tissue cultures as relevant ex vivo model. Conclusion: We identify the induction of ferroptosis as a new mechanism of action of class-I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle besides other, less broadly usable targeted drugs.

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N6-methyladenosine–modified circSLTM inhibits gastric cancer cell proliferation and promotes ferroptosis via interaction with HSPA8

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