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CFH_Interactome : P53 and cell cycle control by an intracellular form of complement Factor H

ABSTRACT: Overexpression of complement genes in the tumor microenvironment, including Factor H (FH), has emerged as a strong predictor of poor patient prognosis. While its canonical role as a negative regulator of the complement cascade is well-known, this alone cannot fully account for this prognostic impact. This study reveals that FH operates in a cascade-independent fashion within fibroblasts and clear cell renal cell carcinoma (ccRCC) tumor cells, where it is overexpressed under pro-tumoral inflammatory conditions. FH prognostic impact stems from its intracellular functions in tumor-promoting fibroblasts and malignant cells. FH, which has a nuclear localization signal, was found in the nucleus, cytosol and organelle fractions of both fibroblasts and ccRCC cells. Co-immunoprecipitation and mass spectrometry identified FH interactions with the cell cycle-transcription factor E2F3. FH accelerates cell cycle progression by preventing p53 activation, potentially through blocking E2F3-p53 interactions at the G1/S transition. In addition, in tumor cells, FH interacts with CapZ to regulate actin cytoskeleton. Finally, transcriptional trajectory analyses of ccRCC malignant cells revealed a CFH enriched cell state linked to proliferation and poor patient prognosis, consistent with increased Ki67 staining in FH-positive cancer cells from patient tumors. Together, these results position FH as a novel tumor-promoting effector of cell cycle through modulation of p53

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Mohamed Ali Jarboui

PROVIDER: MSV000100813 | MassIVE | Wed Feb 11 23:18:00 GMT 2026

SECONDARY ACCESSION(S): PXD074376

REPOSITORIES: MassIVE

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P53 and cell cycle control by an intracellular form of complement Factor H

Project description:Overexpression of complement genes in the tumor microenvironment, including Factor H (FH), has emerged as a strong predictor of poor patient prognosis. While its canonical role as a negative regulator of the complement cascade is well-known, this alone cannot fully account for this prognostic impact. This study reveals that FH operates in a cascade-independent fashion within fibroblasts and clear cell renal cell carcinoma (ccRCC) tumor cells, where it is overexpressed under pro-tumoral inflammatory conditions. FH prognostic impact stems from its intracellular functions in tumor-promoting fibroblasts and malignant cells. FH, which has a nuclear localization signal, was found in the nucleus, cytosol and organelle fractions of both fibroblasts and ccRCC cells. Co-immunoprecipitation and mass spectrometry identified FH interactions with the cell cycle-transcription factor E2F3. FH accelerates cell cycle progression by preventing p53 activation, potentially through blocking E2F3-p53 interactions at the G1/S transition. In addition, in tumor cells, FH interacts with CapZ to regulate actin cytoskeleton. Finally, transcriptional trajectory analyses of ccRCC malignant cells revealed a CFH enriched cell state linked to proliferation and poor patient prognosis, consistent with increased Ki67 staining in FH-positive cancer cells from patient tumors. Together, these results position FH as a novel tumor-promoting effector of cell cycle through modulation of p53.

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