Butin Ameliorates Atherosclerosis by Regulating the TIMM13 ‐ TIMM8A Complex to Alleviate Macrophage Ferroptosis
Year: 2026
Type: article
Abstract: ABSTRACT Atherosclerosis (AS) progression is heavily driven by iron dyshomeostasis and oxidative stress, yet current therapies fail to effectively resolve these underlying drivers. Ferroptosis exacerbates plaque vulnerability through macrophage dysfunction, but its regulatory nodes remain elusive. This study aims to investigate the role of the mitochondrial translocase complex TIMM13/TIMM8A in atherogenesis and evaluate the natural flavonoid Butin as a targeted inhibitor of this complex. Transcriptomic profiling and network pharmacology identified key targets. Oxidized low‐density lipoprotein (Ox‐LDL)‐treated macrophages and high‐fat diet‐fed ApoE −/− mice were used for functional validation. Direct target engagement was demonstrated by Cellular Thermal Shift Assay, molecular dynamics simulations, competitive Co‐Immunoprecipitation, and site‐directed mutagenesis. Ox‐LDL promoted aberrant TIMM13 upregulation and TIMM8A suppression, triggering mitochondrial iron overload and lipid peroxidation; this ferroptotic cascade was exacerbated by TIMM13 overexpression or TIMM8A knockdown. We identified Butin as a selective binder of TIMM13 at the Asn34 residue, competitively disrupting the pathological TIMM13‐TIMM8A interaction. Consequently, Butin restored the SLC7A11/GPX4 axis and alleviated iron overload and inflammation. In ApoE −/− mice, Butin reduced necrotic cores, enhanced plaque stability, and attenuated vascular ferroptosis, whereas in vivo Asn34 mutation abrogated these benefits. This study identifies the TIMM13/TIMM8A complex as a pivotal mitochondrial gatekeeper of ferroptosis in AS, and demonstrates that Butin acts as a targeted natural inhibitor that halts plaque progression by disrupting this complex and restoring iron homeostasis. These findings provide a compelling mechanistic and translational framework for targeting mitochondrial iron handling in cardiovascular disease management.
Source: Phytotherapy Research
DOI: 10.1002/ptr.70495
Institution: First Affiliated Hospital of Zhengzhou University
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,880
OpenAlex ID: W7225632487