Omics · study · 2026
Hepatocyte MLKL Drives Obesity-Driven Hepatocellular Carcinoma Progression via Mitochondrial Dysfunction Independent of Necroptosis in MASLD
Listed in NCBI GEO
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC), particularly in obesity, yet mechanisms linking hepatocyte dysfunction to tumorigenesis remain unclear.
Description
Mixed lineage kinase domain-like protein (MLKL), the effector of necroptosis, is elevated in MASLD, but its hepatocyte-intrinsic role in obesity-driven MASLD-HCC is unknown. Using a long-term Western diet (WD)-induced MASLD-HCC model in hepatocyte-specific MLKL knockout (MlklHepKO) mice, we defined MLKL’s hepatocyte-intrinsic function.
WD increased hepatocyte MLKL protein expression without detectable necroptosis activation, indicating a necroptosis-independent role. MLKL deficiency did not alter WD-induced inflammation, fibrosis, or liver injury but increased hepatic lipid accumulation while reducing lipotoxic lipid species and preserving mitochondrial function. WD-fed MlklHepKO mice developed fewer and smaller tumors with reduced incidence, multiplicity, proliferation, and stemness.
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Transcriptomic analysis revealed upregulation of mitochondrial oxidative phosphorylation pathways in MlklHepKO livers. WD suppressed the mitochondrial fusion protein and tumor suppressor MFN2, whereas MLKL deficiency restored MFN2 expression post-translationally. In HCC cells, MLKL deletion reduced proliferation, improved mitochondrial respiration, and decreased glycolysis; these effects were reversed by MFN2 deletion.
MLKL localized to nuclear and mitochondrial compartments, consistent with organelle-intrinsic functions. The human MLKL inhibitor necrosulfonamide (NSA) suppressed HepG2 xenograft growth, and elevated MLKL expression in human HCC correlated with poorer overall survival. Hepatocyte MLKL promotes MASLD-associated HCC through a non-canonical, RIPK3-independent mechanism involving MFN2 suppression, impaired mitochondrial function, and increased tumor proliferation and stemness.
These findings identify MLKL as a potential therapeutic target in MASLD-associated HCC.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE338nnn/GSE338648 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE338648 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1495312 ncbi.nlm.nih.gov/bioproject/PRJNA1495312 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens · Mus musculus
- From keywords
- Life Sciences
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE338648 | 15 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 (65%) |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| 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[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| 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 |