A new family of bioactive lipids connects cholesterol, cancer and ageing.

When oxidized cholesterol becomes a signal connecting cancer, inflammation and ageing.

Researchers from the INOV team, co-led by Marc Poirot and Sandrine Silvente-Poirot at the Cancer Research Center of Toulouse (CRCT), published a review in Progress in Lipid Research. The review proposes a new conceptual framework for understanding oxidized cholesterol metabolism.

The article defines the epoxycholestanoid (EChA) family. These molecules are derived from 5,6-epoxycholestanols (5,6-ECs), which were long considered accidental by-products of cholesterol oxidation. However, the review shows that these metabolites actually belong to an organized, enzyme-regulated metabolic pathway that can generate potent biological signals. This pathway connects oxidative stress, sterol metabolism, inflammation, and transcriptional control. The pathway is structured around two functionally opposed branches. One branch is pro-proliferative and leads to oncosterone (OCDO). OCDO activates the glucocorticoid receptor (GR) and can promote tumor growth. The other branch is tumor-suppressive and pro-differentiation. It leads to dendrogenin A (DDA). DDA is an endogenous, biased LXRβ ligand involved in cell differentiation, autophagy, neuroprotection, and anti-tumor immunity.

This metabolic balance acts as a cell-fate switch. Depending on the oxidative context, enzyme expression, and inflammatory status, the pathway can direct cells toward proliferation or differentiation. The article emphasizes that dysregulation of this pathway is not restricted to cancer. Dysregulation may also be involved in age-associated diseases, inflammatory and metabolic disorders, cardiovascular disease, neurodegenerative disorders, and lysosomal storage diseases. By defining the EChA family, this publication provides a unifying language for a previously fragmented branch of cholesterol metabolism. The publication also opens important perspectives for biomarker discovery and therapeutic strategies aimed at rebalancing the two branches of the pathway by inhibiting the pro-tumor OCDO-GR axis and reinforcing the DDA-LXRβ axis, which is linked to differentiation, immunity, and neuroprotection.

This publication is a conceptual and mechanistic review; it therefore has no immediate direct clinical impact. However, it identifies several potential targets for clinical application: measurement of EChA metabolites as biomarkers, inhibition of the 11β-HSD2/OCDO/GR axis in cancers where it is activated, and enhancement of the DDA/LXRβ axis associated with differentiation, anti-tumour immunity and neuroprotection. In the longer term, this pathway could contribute to patient stratification in cancer, age-related diseases, inflammatory or metabolic diseases, and certain neurodegenerative diseases.

The priority areas are the identification of DDA synthase, the in vivo validation of the enzymatic formation of 5,6α-EC, the mapping of EChA fluxes using spatial lipidomics and isotopic tracing, and the robust quantification of DDA, CT and OCDO in human tissues and biological fluids. Studies will also need to explore this pathway in cohorts focusing on ageing, inflammatory, metabolic, cardiovascular and neurodegenerative diseases. No patents are reported in the provided publication.

Collaborations and partnerships

Authors:

Julio Buñay, Silia Ayadi, Chloé Gressein, Morjane Boudani, Romane Commerçon, Phuong Le, Laly Pucheu, Michel Record, Philippe de Medina, Sandrine Silvente-Poirot and Marc Poirot.

Affiliations:

INOV team, Toulouse Cancer Research Centre (CRCT), Inserm, CNRS, University of Toulouse.

Funding bodies and support:

Inserm, CNRS, University of Toulouse, National Cancer Institute (PLBIO2020-028, PLBIO2023-050), National Research Agency (DASYNT2, ANR-20-11-0005CE; DASYNT3, ANR-24-44-4332CE), World Cancer Research Foundation (IIG_FULL_2024_015), and the associations ELLES, J’y V, Orange Care and URAFIKI JUU. The team is a member of the NACRe network and the European ENOR network.