Biology subjects

Kolak, A.

Publications and source records attributed to Kolak, A..

2 recordsLinked to original sources

bioRxiv2026

Oxysterol-sensing by Liver X receptor counteracts ferroptosis via lipid remodeling

Ferroptosis, an iron-dependent form of regulated cell death, is controlled by cellular metabolism. Nutrients and metabolites determine cell states that render cells sensitive or resistant to ferroptosis. Nuclear receptors can act as cellular sensors for distinct metabolites and nutrients to regulate ferroptosis. We performed a chemical genetics screen using a nuclear receptor small molecule library to identify novel regulators of ferroptosis. We find that activating or overexpressing the liver X receptor (LXR) suppresses ferroptosis in various cell models, including ex vivo primary mouse hepatocytes. Interestingly, hepatocellular carcinoma with high levels of LXR shows poorer survival outcomes. In cells, activation of LXR by the endogenous oxysterol 24(S),25-epoxycholesterol or synthetic agonists reduces lipid peroxidation and ferroptotic cell death. Mechanistically, LXR activation drives a selective transcriptional program upregulating SREBP-1c, SCD1 and ACSL3, key enzymes involved in the synthesis of monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Lipidomic analysis reveals that this lipid remodeling enriches cellular membranes with MUFA-PLs, reducing their susceptibility to peroxidation and thereby counteracting ferroptosis. Together, we identify LXR as an oxysterol-sensing endogenous suppressor of ferroptosis coupling oxysterol sensing to the adaptive remodeling of cellular membrane lipid composition to limit lipid peroxidation.

cell biology↗

bioRxiv2026

miR-940 suppresses ferroptosis by controlling expression of key regulatory genes

Ferroptosis is a form of regulated cell death that is characterized by iron-dependent lipid peroxidation. This process is regulated by specific metabolites, the lipid composition of the cells, redox-active iron, and antioxidant mechanisms. Although numerous regulators have been identified over the past decade, exploring other mechanisms, particularly from non-coding genomic regions, can build a thorough understanding of the multifaceted regulatory processes underlying ferroptosis. MicroRNAs (miRNAs) play a crucial role in gene regulation and cellular functions. Through a CRISPR KO screen, we identified miR-940 as a negative regulator of ferroptosis. Overexpression of miR-940 in several cell lines consistently suppressed ferroptosis induced by system xc- inhibition. Notably, multiple cancer patient cohorts with elevated miR-940 levels exhibit reduced survival. Integrated bioinformatic, transcriptomic, and proteomic analyses revealed that miR-940 decreases the expression of ACSL4, LPCAT3, DMT1, and NCOA4, and simultaneously increases levels of GPX4. Pharmacological inhibition of GPX4 attenuated the protective effect of miR-940, indicating that its primary anti-ferroptotic activity is mediated through GPX4. Overall, this gene rewiring is associated with reduced levels of redox-active iron and diminished lipid peroxidation, consistent with ferroptosis suppression. These findings suggest that miR-940 coordinates ferroptosis inhibition, which presents a novel regulatory layer for therapeutic exploration in susceptible cancers.

cell biology↗