Bawa, O. | bioRxiv Science

bioRxiv2025

Engineered flavonoid disrupts mitochondrial AIF/CHCHD4 complex for targeted cancer therapy

Oncogenic metabolism depends on multifaceted mechanisms, including bidirectional inter-organelle communication between mitochondria and the nucleus, facilitating cellular adaptation at the transcriptomic, proteomic, and metabolomic levels. The mitochondrial protein complex composed of apoptosis-inducing factor (AIF) and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is essential for this mitochondrio-nuclear communication. The AIF/CHCHD4 complex mediates the mitochondrial import of cysteine-enriched nuclear gene-encoded proteins, thereby adapting the mitochondrial proteome to cellular energy demands. We report the discovery of M30-E05, an engineered flavonoid that binds to the NADH pocket of AIF, preventing its dimerization and disrupting the AIF/CHCHD4 complex. Molecular docking and gel electrophoresis analysis of mitochondrial AIF/CHCHD4 substrates expression confirm this mechanism. In cancer cells, M30-E05 reduces the expression of nuclear gene-encoded mitochondrial proteins such as AIF, CHCHD4, COX17, and MICU1. In addition, M30-E05 fragments the mitochondrial network and impairs mitochondrial respiration, causing profound alterations, particularly in lipid and aminoacid metabolism, as revealed by kinetic measurements of oxygen consumption and mass spectrometric metabolomics. Importantly, M30-E05 significantly reduces the viability of a human adult and pediatric osteosarcoma cancer cell panel, including those from patient-derived xenografts (PDX) of osteosarcomas, and induces apoptosis. When orally administered for two weeks to immunodeficient NSG mice, M30-E05 inhibited tumor growth in a subcutaneous PDX xenograft model without apparent toxicity. We anticipate that M30-E05, as a first-in-class metabolic inhibitor, could serve as the lead compound for a new class of targeted antineoplastic agents. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/642976v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1b1add9org.highwire.dtl.DTLVardef@cac7corg.highwire.dtl.DTLVardef@101c9corg.highwire.dtl.DTLVardef@1c6845f_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2022

TGFβ receptor inhibition unleashes interferon-β production by tumor-associated macrophages and enhances radiotherapy efficacy

BackgroundTransforming growth factor-beta (TGF{beta}) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGF{beta} with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGF{beta} participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations. MethodsWe used the clinically relevant TGF{beta} receptor 2 (TGF{beta}R2)-neutralizing antibody MT1 and the small molecule TGF{beta}R1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer. ResultsWe demonstrated that TGF{beta} pathway inhibition strongly increased the efficacy of RT. TGF{beta}R2 antibody upregulated interferon beta (IFN{beta}) expression in tumor-associated macrophages (TAMs) within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and inhibition of immune exclusion observed with the combination of MT1 and RT were dependent on type I interferon signaling. ConclusionsThese data shed new light on the role of TGF{beta} in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGF{beta}R inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer.

cancer biology↗