bims-hafaim 2026-02-15 papers

Issue of 2026–02–15
four papers selected by
Kyle McCommis, Saint Louis University

Clin Sci (Lond). 2026 Feb 09. pii: CS20256032. [Epub ahead of print]

Targeting Perilipin 5 Ameliorates Diabetic Cardiomyopathy via Regulating Glycolysis and Mitochondrial Dynamics.

This study investigates how Perilipin 5 (Plin5), a lipid droplet-associated protein crucial for regulating intracellular lipid metabolism, modulates glycolysis, apoptosis, and mitochondrial function under high glucose conditions, with a focus on its therapeutic potential in Diabetic cardiomyopathy (DCM). AC16 human cardiomyocyte cells and human cardiac fibroblasts (HCFs) were transfected with Plin5-overexpressing lentivirus. An in vivo DCM model was established in wild-type and Plin5-knockout mice using a high-fat diet (HFD) combined with streptozotocin (STZ) injection. Cardiac function was evaluated, and cellular mechanisms were assessed using molecular biology techniques and single-cell RNA sequencing analysis. Plin5 overexpression significantly enhanced glycolysis (e.g., a 2.5-fold increase in extracellular acidification rate, p<0.001) in both AC16 and HCFs. In AC16 cells, high glucose treatment upregulated Plin5 expression, whereas in HCFs, it led to downregulation. Apoptosis-related protein levels, including BCL-2 and cleaved Caspase-3, were modulated by Plin5 overexpression, with a notable impact under high glucose conditions. Cardiac ultrasound revealed significant differences in systolic function (EF values) across experimental groups. Ki67 staining showed enhanced cardiomyocyte proliferation in Plin5-overexpressing groups under normal glucose conditions, while TUNEL assays indicated reduced apoptosis, though this effect was attenuated under high glucose conditions. Bioinformatics analysis revealed a significant upregulation of fatty acid metabolism pathways in the diabetic heart, with Plin5 expression specifically increased in cardiomyocytes. In summary, this study demonstrates that Plin5 plays a critical role in regulating glycolysis, apoptosis, and cardiomyocyte proliferation, particularly under varying glucose conditions, identifying it as a potential therapeutic target for DCM.

Keywords: Apoptosis; Cardiac metabolism; Diabetic cardiomyopathy; Exercise; Glycolysis; Metabolic Reprogramming; Metabolic regulation; Mitochondrial dysfunction; Mitochondrial function; Perilipin 5

DOI: https://doi.org/10.1042/CS20256032

Br J Pharmacol. 2026 Feb 11.

The NADPH oxidase inhibitor Vas2870 prevents myocyte ferroptosis and improves cardiac remodelling and function in doxorubicin-induced cardiomyopathy.

Jing Wang, Chen-Mo-Zhen Li, Bin Yang, Run-Nan Tantai, Hong-Xia Guo, Hui-Ping Zhao, Xiao-Juan Zhang, Fei Wang, Fu-Zhong Qin, Bao Li, Jia-Pu Wang.

BACKGROUND AND PURPOSE: Doxorubicin has been used widely for the treatment of human cancer but its clinical use is limited by cardiotoxicity. We examined the effect of the pan-NADPH oxidase inhibitor Vas2780 on myocyte ferroptosis and cardiac remodelling and function in a clinically relevant mouse model of chronic doxorubicin-induced cardiomyopathy and the underlying mechanisms.
EXPERIMENTAL APPROACH: Sixty-five mice were randomized to receive saline, Vas2870 (2 mg·kg-1, i.p., once a day for 40 days), doxorubicin (3 mg·kg-1, i.p., every other day, six times) or doxorubicin plus Vas2870 (n = 10-22).
KEY RESULTS: Doxorubicin-treated mice exhibited a decrease in left ventricular (LV) fractional shortening and an increase in the ratio of lung wet-to-dry weight, indicating LV systolic dysfunction and lung congestion, and these alterations were prevented by the Vas2870 treatment. In doxorubicin-treated mice, myocardial levels of gp91phox, malondialdehyde and 4-hydroxynonenal were increased; SLC7A11, GPX4, FTH1 and FPN proteins were decreased; TfR1 (CD71) protein and myocardial iron levels were elevated and ALAS1 was reduced. Vas2870 inhibited myocardial lipid peroxidation, prevented decreased SLC7A11 and GPX4 proteins, normalized dysregulated iron metabolism-related proteins, increased ALAS1 protein and upregulated mitochondrial genes, resulting in the prevention of iron overload and ferroptosis in doxorubicin-induced cardiomyopathy. Similarly, Vas2870 prevented doxorubicin-induced ferroptosis in H9C2 cardiomyocytes.
CONCLUSION AND IMPLICATIONS: Vas2870 prevents myocyte ferroptosis through inhibition of lipid peroxidation, GPX4/SLC7A11 downregulation and disruptions in iron metabolism, leading to the amelioration of doxorubicin-induced heart failure. Therapies directed at inhibiting NADPH oxidase and/or ferroptosis may be of value in the treatment of heart failure.

Keywords: NADPH oxidase; Vas2870; cardiomyopathy; doxorubicin; ferroptosis

DOI: https://doi.org/10.1111/bph.70352

Exp Ther Med. 2026 Mar;31(3): 84

Effect of SGLT2 inhibitors on heart failure outcomes in patients with and without diabetes: A systematic review and meta-analysis of randomized controlled trials.

Duaa Abdullah Bafail, Noura Hamdi Alhalees.

Heart failure (HF) is a debilitating condition with high morbidity and mortality rates worldwide. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exhibit cardiovascular (CV) and renal protective effects beyond glucose lowering, and may serve a role in managing HF across numerous patient populations, including non-diabetics. Therefore, the present systematic review and meta-analysis aimed to evaluate the efficacy of SGLT2i in reducing HF hospitalizations, CV mortality and adverse events in patients with and without type 2 diabetes mellitus. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, comprehensive literature searches were conducted across PubMed, Scopus, Web of Science and Cochrane Central databases up to May 2025. Randomized controlled trials (RCTs; phases II-IV) enrolling adults with HF, irrespective of ejection fraction or diabetes status, comparing SGLT2i with placebo or standard-of-care were included in the present study. Outcomes analyzed encompassed HF hospitalizations, CV and all-cause mortality, adverse events and patient-reported quality of life measures. Meta-analysis was performed with RevMan 5.4 using a random-effects model. Data from 28 RCTs, including numerous high-quality trials, consistently demonstrated that SGLT2i significantly reduced the risk of first and total hospitalization for HF by 24% [odds ratio (OR)=0.76; 95% CI: 0.64-0.91; P=0.002; I²=0%] and 33% (OR=0.67; 95% CI: 0.63-0.72; P<0.00001; I²=33%), respectively. In addition, the use of SGLT2i decreased all-cause and CV-associated mortality by 28% (OR=0.72; 95% CI: 0.61-0.86; P=0.0002; I2=88%) and 24% (OR=0.76; 95% CI: 0.70-0.83; P<0.00001; I²=57%), respectively. Furthermore, adverse events occurred in 22% (OR=0.78; 95% CI: 0.59-1.02; P=0.07; I2=97%), regardless of the diabetic status of the patients. Publication bias was significant (P<0.05) in studies addressing total hospitalization, while studies evaluating all-cause mortality, CV-associated mortality and adverse events did not exhibit significant publication bias (P≥0.05). The majority of studies were found to have a low risk of bias, with only a small number of studies exhibiting a high risk of bias. Low-to-high certainty of evidence was observed. Overall, SGLT2i were indicated to be effective in reducing hospitalization for HF and improving survival in a broad spectrum of patients, including those without diabetes. The multifactorial mechanisms of SGLT2i are likely to contribute to these benefits, supporting their emerging role in HF management.

Keywords: cardiovascular mortality; diabetes mellitus; ejection fraction; heart failure; hospitalization; sodium-glucose cotransporter 2 inhibitors

DOI: https://doi.org/10.3892/etm.2026.13079

bioRxiv. 2026 Feb 04. pii: 2026.02.02.702681. [Epub ahead of print]

Metabolic Flexibility and Energy Substrate Utilization Regulate Contractility in the Human Myometrium.

Kevin K Prifti, Ritu M Dave, Kaci T Mitchum, Jordan L Rich, Ruth M Gill, Magdaleena N Mbadhi, Antonina I Frolova.

The uterus requires energy for sustained contractility during labor, to deliver the fetus and diminish the risk of postpartum hemorrhage. Our objective was to define energy requirements and assess metabolic flexibility in quiescent and contractile myometrial cells. Cells were treated with oxytocin to stimulate myometrial contractility. We found that myometrial cells rely on oxidative phosphorylation during quiescence and, when treated with oxytocin, can adapt to higher energy demands by shifting their energy production to glycolysis. Treatment with mitochondrial oxidation inhibitors revealed that in quiescent myometrial cells basal oxygen consumption rate decreased when treated with glucose oxidation inhibitor UK5099, but not the long chain fatty acid oxidation inhibitor etomoxir or the glutamine oxidation inhibitor BPTES. In oxytocin treated myometrial cells, this decrease was also observed upon BPTES treatment in addition to UK5099, suggesting that contractile myometrial cells can shift energy production from glucose to glutamine. Functionally, myometrial contractility was significantly reduced by UK5099 but not by etomoxir, further indicating dependence on glucose utilization.

DOI: https://doi.org/10.64898/2026.02.02.702681