bims-hafaim 2026-02-08 papers

Issue of 2026–02–08
four papers selected by
Kyle McCommis, Saint Louis University

bioRxiv. 2026 Jan 12. pii: 2026.01.12.698694. [Epub ahead of print]

Unrestrained fatty acid oxidation triggers heart failure in mice via cardiolipin loss and mitochondrial dysfunction.

Chai-Wan Kim, Goncalo Vale, Xiaorong Fu, Jeffrey McDonald, Chongshan Dai, Chao Li, Zhao V Wang, Gaurav Sharma, Chalermchai Khemtong, Craig Malloy, Stanislaw Deja, Shawn C Burgess, Matthew Mitsche, Jay D Horton.

Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.

DOI: https://doi.org/10.64898/2026.01.12.698694

iScience. 2026 Feb 20. 29(2): 114610

Integrative insights into fatty acid metabolism in diabetic cardiomyopathy: From molecular mechanisms to therapeutic strategies.

Shiying Chen, Xiaofang Zhang, Tiantian Lu, Hui Lin, Xinrou Yu, Jun Wang, Dajun Lou, Dihua Huang.

Diabetic cardiomyopathy (DCM) is a diabetes-specific cardiac dysfunction independent of other cardiovascular diseases. Recent studies highlight dysregulated fatty acid (FA) metabolism as a central driver of its pathogenesis. In the diabetic heart, excessive FA uptake and oxidation imbalance with glucose utilization led to lipid accumulation, mitochondrial overload, and oxidative stress. These changes trigger inflammatory responses, impair mitochondrial structural integrity and quality control, and disrupt cellular energy homeostasis. Over time, this maladaptation promotes cardiomyocyte hypertrophy, interstitial fibrosis, and progressive diastolic dysfunction. This review synthesizes current knowledge on the links between FA metabolic dysregulation and DCM, from metabolic overload to structural remodeling. It also discusses emerging therapeutic strategies aimed at reducing pathological lipid influx, optimizing energy substrate balance, restoring mitochondrial function, and preventing downstream injury, with the goal of guiding precision interventions for DCM.

Keywords: health sciences

DOI: https://doi.org/10.1016/j.isci.2025.114610

iScience. 2026 Feb 20. 29(2): 114639

Thrombospondin 1 aggravates cardiac remodeling in heart failure with preserved ejection fraction by inhibiting mitophagy.

Xingpeng Bu, Shuo Sha, Zhenzhen Zhang, Sicheng Bian, Shuhui Feng, Chunxia Li, Lei Wang, Huanzhen Chen.

Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases, but its underlying mechanisms remain unclear. Mitochondrial dysfunction and defective mitophagy are increasingly recognized as central features of HFpEF. Thrombospondin 1 (Thbs1), a matricellular protein involved in cardiovascular remodeling, has not been explored in this context. Here, we show that Thbs1 expression is elevated in HFpEF myocardium and that Thbs1 aggravates cardiac dysfunction by inhibiting mitophagy. In a "two-hit" HFpEF mouse model induced by high-fat diet and L-NAME, AAV9-mediated Thbs1 knockdown improved diastolic function, reduced fibrosis and inflammation, and mitigated PI3K/Akt/mTOR pathway activation revealed by transcriptomic and proteomic profiling. Mechanistically, Thbs1 silencing restored autophagic flux, enhanced mitochondrial clearance, and preserved mitochondrial homeostasis in cardiomyocytes. These findings identify Thbs1 as a key suppressor of mitophagy in HFpEF and a potential therapeutic target for this prevalent condition.

Keywords: Cell biology; Model organism; Omics

DOI: https://doi.org/10.1016/j.isci.2026.114639

Circulation. 2026 Feb 06.

Insulin Resistance Compromises the Pentose Phosphate Pathway and Impairs Left Ventricular Assist Device-Mediated Myocardial Recovery in Obese Patients with Heart Failure.

BACKGROUND: End-stage heart failure (HF) remains a major global health challenge, and left ventricular assist devices (LVADs) represent an important therapeutic option. LVAD-mediated mechanical unloading improves cardiac function and promotes myocardial recovery in many patients with HF. How cardiac unloading by LVADs leads to myocardial recovery and whether impairment of these processes underlies the limited myocardial recovery benefit in obese patients remain poorly understood.
METHODS: Patients with HF with LVADs were recruited for an investigation of the correlation between patients' body mass index and their response to LVAD-mediated myocardial recovery. Moreover, a mouse model of heterotopic cervical heart transplantation was used to simulate LVAD unloading. Single-nucleus RNA sequencing and stable-isotope tracing metabolomics were performed to explore the changes of signaling pathways and metabolic processes in unloaded hearts. In vitro cyclic stretch assays were used to evaluate how reduced mechanical load regulates cardiomyocyte metabolic pathways. Unloaded hearts from HF mice were used to determine whether the identified metabolic process contributed to unloading-induced myocardial recovery. Furthermore, the unloaded hearts from obese HF mice were used to evaluate whether the identified metabolic process was attenuated by obesity.
RESULTS: HF patients with a higher body mass index (≥28.0) and greater insulin resistance tended to have poorer LVAD-mediated myocardial recovery. Single-nucleus RNA sequencing demonstrated that mechanical unloading activated myocardial insulin signaling and increased glucose uptake. Stable-isotope tracing metabolomics revealed that glucose taken up by unloaded hearts was preferentially diverted into the pentose phosphate pathway. Mechanistically, reduced mechanical stress attenuated Hippo pathway activation in cardiomyocytes, facilitating insulin signaling and enhancing pentose phosphate pathway flux. The unloaded hearts from HF mice revealed that an increase in pentose phosphate pathway flux could reduce oxidative stress and exert cardioprotective effects. However, these benefits were blunted by insulin resistance in obese mice, whereas treatment with insulin sensitizers alleviated insulin resistance and restored unloading-mediated cardioprotection.
CONCLUSIONS: In failing hearts, unloading leads to activation of insulin signaling, resulting in increased glucose uptake and an enhanced pentose phosphate pathway to protect cardiomyocytes against oxidative stress. However, this cardioprotective effect is attenuated by obesity-induced insulin resistance. Administration of insulin sensitizers has the potential to improve LVAD-mediated myocardial recovery in obese patients with HF.

Keywords: LVAD; insulin resistance; myocardial recovery; pentose phosphate pathway

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.072850