Omics · study · 2026
TMEM97 is A Cholesterol Sensing Onco-Protein and Sustains Mitochondrial Energetics Through Lipid Biosynthesis
Listed in NCBI GEO
Despite advanced therapeutics, gastric carcinoma is still a leading cause of cancer mortality.
Description
Investigating metabolic vulnerabilities has become crucial to identify new drug targets and to develop biomarkers for monitoring disease progress. The aim of this study is to investigate the functional role of TMEM97 in the cholesterol metabolism and carcinogenesis.
We demonstrated that TMEM97 ablation substantially reduced in vitro cell proliferation and impaired tumor growth in xenograft models. Furthermore, TMEM97 deficiency disrupted cholesterol homeostasis. Untargeted metabolomics identified a significant accumulation of the post-lanosterol intermediate follicular fluid meiosis-activating sterol (FF-MAS) in KO cells under both normal and lipoprotein-deficient serum (LPDS) conditions, implying a bottleneck in cholesterol biosynthesis beyond lanosterol.
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Notably, TMEM97 KO cells showed compensatory upregulation of key regulatory enzymes HMGCR and SQLE, alongside enhanced expression of sterol regulatory element-binding proteins (SREBP1/2), suggesting a regulatory feedback loop. Additionally, the loss of TMEM97 induced broader metabolic reprogramming as multi-omic analysis revealed impaired TCA cycle with altered levels of intermediates, gene expressions and decreased mitochondrial oxygen consumption rate (OCR), particularly under LPDS conditions.
Structural analysis revealed a conserved cholesterol recognition/interaction amino acid consensus (CARC) motif in TMEM97, and the deletion of this motif substantially reduced cholesterol binding in vitro. To conclude, TMEM97 senses cholesterol availability and modulates SREBP-mediated transcriptional responses to lipid availability. Loss of TMEM97 impairs post-lanosterol cholesterol biosynthesis, alters lipid profiles, and disrupts mitochondrial bioenergetics.
Given its tumorigenic role and druggability, TMEM97 delineated as a novel drug target for gastric carcinoma.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE312nnn/GSE312758 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312758 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1375822 ncbi.nlm.nih.gov/bioproject/PRJNA1375822 ↗
project · from NCBI GEO
- PubMed 42519026 pubmed.ncbi.nlm.nih.gov/42519026 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Biochemistry and cell biology 68% · Cancer 75% · Disease 75% · Optical character recognition 65%
Provenance · 1 source records, 11 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE312758 | 12 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].anzsrc:group:3101 | enrichment · NCBI GEO | taxonomy-embedding@1.1.0 | title+keywords+description (68%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[method].local:method:ocr | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |