Biology subjects

Tyurina, Y. Y.

Publications and source records attributed to Tyurina, Y. Y..

3 recordsLinked to original sources

bioRxiv2026

Hydroperoxy-lipids Are Essential Yet Insufficient For Execution Of Ferroptosis

Cells with irreparable redox disbalance in membranes trigger a program of regulated death - ferroptosis. 15-lipoxygenase (LOX)-catalyzed accumulation of hydroperoxy-phosphatidyl-ethanolamines (HOO-PEs) has been associated with the execution of ferroptosis; yet, experimental proof of their sufficiency is lacking. Using the Fe-independent hydrophobic radical initiator, 2,2'-azobis(2,4-dimethyl)-valeronitrile (AMVN), we demonstrate that the accumulation of hydroperoxy-phospholipids (HOO-PLs) is necessary, but insufficient for driving ferroptosis. We further show that Fe-catalyzed decomposition of HOO-PLs into radical intermediates and oxidatively truncated (OxTr) electrophilic species, as well as the formation of protein adducts with OxTr electrophilic species are required for the completion of the ferroptotic program. Consequently, three types of agents - inhibitors of LOXs and other enzymatic generators of HOO-PLs, radical scavengers, and small-molecule nucleophiles - acting at different stages of lipid peroxidation during the ferroptotic program represent effective and specific ferroptosis regulators and potential therapeutic remedies.

biochemistry↗

bioRxiv2024

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression

AbstractOvarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor- associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor Rbhigh M2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape. Statement of significanceCurrently, targeting immunosuppressive myeloid cells in ovarian cancer microenvironment is the first priority need to enable successful immunotherapy, but no effective solutions are clinically available. We show that targeting LxCxE cleft pocket of Retinoblastoma protein unexpectedly induces preferential cell death in M2 tumor-associated macrophages. Depletion of immunosuppressive M2 tumor-associated macrophages reshapes tumor microenvironment, enhances anti-tumor T cell responses, and inhibits ovarian cancer. Thus, we identify a novel paradoxical function of Retinoblastoma protein in regulating macrophage viability as well as a promising target to enhance immunotherapy efficacy in ovarian cancer.

immunology↗

bioRxiv2019

Conjugated linolenic fatty acids trigger ferroptosis in triple-negative breast cancer

Ferroptosis is a non-apoptotic form of cell death linked to the accumulation of reactive hydroperoxides generated by oxidation of polyunsaturated fatty acids (PUFAs) in membrane phospholipids. The therapeutic potential of promoting ferroptosis by enriching PUFAs in cancer cells is unknown. We found an association between elevated PUFA levels and vulnerability to ferroptosis in triple-negative breast cancer (TNBC) cells. A screen of PUFAs identified conjugated linolenic acids, including -eleostearate, as ferroptosis inducers. Three conjugated double bonds were required for ferroptotic activity although their positioning and stereochemistry were less significant. Mechanistically, -eleostearate differed from canonical ferroptosis inducers by a distinct dependence on acyl-CoA synthetase long-chain isoforms and by not altering glutathione or glutathione peroxidase 4 activity. Orally administered tung oil, naturally rich in -eleostearate, limited tumor growth and metastasis in an aggressive TNBC xenograft model. These results expand our understanding of ferroptotic cell death and highlight the anti-cancer potential of conjugated PUFAs.

cancer biology↗