bims-hafaim 2026-08-23 papers

Issue of 2026–08–23
three papers selected by
Kyle McCommis, Saint Louis University

Phytomedicine. 2026 Aug 13. pii: S0944-7113(26)00949-9. [Epub ahead of print]161 158718

A novel polysaccharide from Ligusticum chuanxiong attenuates cardiac hypertrophy by targeting ferroptosis through the SIRT3-mediated deacetylation of Foxo3a.

Lei Chen, Zhuang Chen, Chengjie Song, Zhi Li, Yixuan Wu, Yiwen Wang, Weiwei Sha, Dongchen Liu, Jue Xi, Yuan Lu.

BACKGROUND: Pathological cardiac hypertrophy is a maladaptive response to pressure overload that frequently leads to heart failure, highlighting the urgent need for effective therapies. Plant-derived polysaccharides are promising bioactive candidates due to their safety and pleiotropic effects. Although Ligusticum chuanxiong has long been used for cardiovascular diseases, the structural features and mechanisms of its polysaccharides in cardiac hypertrophy remain unclear.
PURPOSE: To isolate and characterize a novel polysaccharide from Ligusticum chuanxiong and elucidate its protective effects and molecular mechanism against pressure overload-induced cardiac hypertrophy.
STUDY-DESIGN/METHODS: A homogeneous polysaccharide (FL-D2N1) was purified and structurally characterized by FT-IR, monosaccharide analysis, glycosidic linkage analysis, NMR, and SEC-MALLS-RI. Its in vivo cardioprotective effects were evaluated in TAC-induced heart failure mice by assessing cardiac function, hypertrophy, fibrosis, and ferroptosis. Transcriptomic profiling and mechanistic validation identified key pathways. In vitro, Ang II-stimulated cardiomyocytes were used to examine mitochondrial function, ferroptosis, mitophagy, dynamics, and energy metabolism. The SIRT3/Foxo3a axis was validated using pharmacological tools, immunofluorescence, immunoprecipitation, and SIRT3 siRNA.
RESULTS: A novel galactan-type polysaccharide, FL-D2N1, was successfully isolated from Ligusticum chuanxiong rhizomes, exhibiting a weight-average molecular weight of 94.376 kDa and adopting a compact spherical conformation in aqueous solution. Structural elucidation revealed a highly branched architecture featuring a backbone of →6)-β-D-Galp-(1→, →3)-β-D-Galp-(1→, and →3,6)-β-D-Galp-(1→ residues, with α-L-Araf-(1→ units as side chains. In TAC-induced mice, FL-D2N1 administration markedly enhanced cardiac function, alleviated ventricular remodeling, diminished hypertrophy and fibrosis, and inhibited myocardial ferroptosis, as evidenced by decreased MDA and iron accumulation and restored GSH levels. Transcriptomic analysis coupled with mechanistic validation pinpointed SIRT3 as a central hub regulating FL-D2N1-conferred cardioprotection. FL-D2N1 upregulated SIRT3 expression alongside its deacetylase activity, facilitating Foxo3a deacetylation and subsequent transcriptional modulation of antioxidant and anti-ferroptotic programs. Functionally, FL-D2N1 enhanced PINK1/Parkin-mediated mitophagy, restored mitochondrial dynamics via MFN2 upregulation and Drp1 Ser616 dephosphorylation, preserved mitochondrial ultrastructure and membrane potential, reduced mitochondrial ROS overproduction, and improved mitochondrial respiratory function. Notably, SIRT3 silencing using specific siRNA abrogated the protective effects of FL-D2N1 on ferroptosis suppression, mitophagy enhancement, and mitochondrial preservation, confirming the indispensable function of the SIRT3/Foxo3a axis in its mechanism of action.
CONCLUSION: FL-D2N1, a novel galactan from Ligusticum chuanxiong, attenuates pathological cardiac hypertrophy by suppressing ferroptosis and preserving mitochondrial quality control via the SIRT3/Foxo3a axis. This structurally defined natural polysaccharide represents a promising candidate for preventing and treating cardiac hypertrophy and heart failure.

Keywords: Cardiac hypertrophy; Ferroptosis; Ligusticum chuanxiong; Mitochondrial function; Polysaccharide; SIRT3/Foxo3a deacetylation axis

DOI: https://doi.org/10.1016/j.phymed.2026.158718

Front Cardiovasc Med. 2026 ;13 1917012

Gut-derived metabolites and mitochondrial homeostasis in heart failure: mechanistic links and translational perspectives.

Daqiu Chen, Mingxuan Su, Zhanxiong Xie, Shanghua Xu, Shunxiang Luo.

Heart failure is a chronic cardiovascular syndrome with high morbidity and mortality worldwide, and its progression is closely linked to myocardial metabolic remodeling and disruption of mitochondrial homeostasis. Increasing evidence suggests that the gut microbiota and its metabolites represent an important interface between diet, inflammation, metabolic stress, and cardiovascular remodeling. Gut-derived metabolites, including short-chain fatty acids, trimethylamine N-oxide, tryptophan-derived metabolites, bile acids, phenylacetylglutamine, indoxyl sulfate, and urolithins, may influence myocardial mitochondrial homeostasis by affecting substrate oxidation, oxidative phosphorylation, reactive oxygen species production, inflammatory signaling, mitochondrial dynamics, mitophagy, and cell-death pathways. However, these metabolites should not be interpreted as uniformly protective or detrimental, because their biological effects may depend on concentration, exposure duration, bioavailability, protein binding, renal clearance, cellular targets, host metabotype, experimental model, and heart failure phenotype. Short-chain fatty acids and indole-3-propionic acid (IPA) have been linked to mitochondrial oxidative metabolism, nicotinamide adenine dinucleotide (NAD+)/sirtuin 3 (SIRT3)-related mitochondrial signaling, and inflammatory regulation in selected experimental settings, whereas the choline/trimethylamine N-oxide axis, indoxyl sulfate, phenylacetylglutamine, and dysregulated bile acid metabolism are associated with myocardial fibrosis, oxidative stress, mitochondrial dysfunction, and adverse outcomes. Nevertheless, many clinical associations may be influenced by renal dysfunction, disease severity, and heart-to-gut reverse causality, and many mechanistic findings remain derived from animal models, ex vivo systems, or non-classical heart-failure models. This narrative review summarizes current evidence linking gut-derived metabolites to myocardial mitochondrial homeostasis in heart failure, with emphasis on energy metabolic remodeling, oxidative stress, inflammation, mitochondrial quality control, cell death, and fibrotic remodeling. Potential intervention strategies targeting the gut microbiota and its metabolic pathways are also discussed with attention to their translational limitations and to the need for direct mitochondrial readouts, cell-type-specific validation, and phenotype-specific clinical studies.

Keywords: context-dependent effects; gut microbiota; gut-derived metabolites; heart failure; mitochondrial quality control; myocardial mitochondrial homeostasis; short-chain fatty acids; trimethylamine N-oxide

DOI: https://doi.org/10.3389/fcvm.2026.1917012

Redox Biol. 2026 Aug 12. pii: S2213-2317(26)00349-6. [Epub ahead of print]96 104350

Myocilin drives cardiomyocyte mitochondrial dysfunction via SLC3A2-dependent redox imbalance in heart failure.

Xiaoyue Yu, Junxia Zhang, Junfang Wu, Mingming Zhao, Hongtu Cui, Sen Huang, Jiawen Liu, Minwen Long, Yandong Pei, Aiming Liu, Jinwei Tian, Chen Chen, You-Yi Zhang, Er-Dan Dong, Han Xiao.

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide. A hallmark of HF progression is profound metabolic remodeling accompanied by mitochondrial dysfunction in cardiomyocytes. Impaired mitochondrial oxidative phosphorylation, excessive reactive oxygen species (ROS) production, and disrupted redox homeostasis collectively drive oxidative damage and compromise mitochondrial integrity, ultimately leading to contractile failure, for which no viable strategies currently exist. Although mitochondrial dysfunction is now recognized as a central driver of HF pathogenesis, the upstream molecular regulators that initiate or amplify these defects remain incompletely understood. Here, we identify myocilin as a fibroblast-derived mediator that drives cardiomyocyte mitochondrial dysfunction and ROS production in HF. Myocilin was consistently upregulated in patients with HF and in murine HF models induced by transverse aortic constriction and isoproterenol, and was predominantly expressed in cardiac fibroblasts. In vivo study using male mice showed that myocilin overexpression exacerbated cardiac dysfunction and fibrosis, whereas genetic ablation markedly alleviated pathological remodeling. Using transwell systems and recombinant protein stimulation, we found that fibroblast-derived myocilin impaired mitochondrial function in cardiomyocytes, as evidenced by reduced ATP production, increased ROS, and loss of membrane potential. Mechanistically, myocilin directly interacted with SLC3A2, the heavy chain that pairs with SLC7A11 to form the cystine/glutamate antiporter, on cardiomyocytes and promoted its degradation, thereby impairing cystine uptake. This led to glutathione depletion and redox imbalance, subsequently triggering ferroptosis-associated mitochondrial dysfunction in cardiomyocytes. Collectively, these findings identify a fibroblast-cardiomyocyte signaling axis in which myocilin disrupts cardiomyocyte metabolic homeostasis. Targeting the myocilin-SLC3A2 pathway may represent a potential therapeutic strategy for HF.

Keywords: Heart failure; Mitochondrial dysfunction; Myocilin; Oxidative stress; Paracrine communication; SLC3A2

DOI: https://doi.org/10.1016/j.redox.2026.104350