Jul 2026· World Journal of Diabetes· 0 citations· 192 references
TL;DR
Given the multifactorial nature of DCM, combination therapies targeting ferroptosis and mitochondrial dysfunction may offer superior outcomes, and future drug development should prioritize agents that precisely regulate these interrelated pathways, enabling personalized treatment strategies for DCM.
Abstract
Diabetic cardiomyopathy (DCM) is a common diabetes-related complication that can progress to heart failure. Early-stage DCM is asymptomatic, requiring advanced imaging for diagnosis, and currently lacks approved targeted therapies, highlighting the urgent need for DCM-specific drugs. Emerging evidence suggests that iron homeostasis imbalance and mitochondrial dysfunction are closely interconnected and synergistically drive DCM onset and progression. This review provides a comprehensive overview of the molecular interplay between ferroptosis and mitochondrial damage in DCM and evaluates the therapeutic potential of three intervention categories: (1) Standard glucose-lowering agents; (2) Novel mechanism-targeted therapies (iron chelators, mitochondrial protectants); and (3) Multi-targeting traditional Chinese medicine (TCM) and their bioactive compounds. While Sodium-glucose co-transporter-2 inhibitors and other antidiabetic drugs provide modest protection against DCM progression, they exhibit limited efficacy, do not fully restore mitochondrial function, and are associated with adverse effects. Emerging targeted therapies such as iron chelators and mitochondrial protectants face safety concerns and lack extensive clinical validation, with their potential drug-drug interactions remaining uncertain. In contrast, selected TCM-derived bioactive compounds have shown cardioprotective potential through multi-target regulation of ferroptosis and mitochondrial homeostasis in preclinical DCM models. Additional TCM with demonstrated efficacy in ferroptosis and mitochondrial function are also reviewed. Given the multifactorial nature of DCM, combination therapies targeting ferroptosis and mitochondrial dysfunction may offer superior outcomes. Future drug development should prioritize agents - whether synthetic or natural - that precisely regulate these interrelated pathways, enabling personalized treatment strategies for DCM.
Sepsis-induced cardiomyopathy (SIC), a severe complication of sepsis, is strongly associated with significantly increased patient mortality, yet targeted therapeutic strategies remain lacking. Emerging evidence has established ferroptosis, an iron-dependent, lipid peroxidation-mediated regulated cell death pathway, as a critical pathogenic mechanism underlying SIC. Iron metabolism dysregulation plays a central role in SIC. Although sepsis reduces circulating iron levels, iron paradoxically accumulates in myocardial tissues. This abnormal redistribution of iron leads to uncontrollable lipid peroxidation in cardiac tissue, ultimately aggravating myocardial injury. In recent years, the application of traditional Chinese medicine (TCM) in the treatment of sepsis has become increasingly widespread. Moreover, due to its multi-target and multi-pathway advantages, TCM has shown considerable potential in the intervention of ferroptosis. However, due to the lack of understanding of the precise molecular mechanism, the therapeutic potential of TCM and its active components in SIC has not been fully explored. This review summarizes the mechanism of ferroptosis in the pathogenesis of SIC, and comprehensively synthesizes the mechanism and application potential of TCM targeting ferroptosis for SIC intervention, aiming to provide a theoretical basis for the development of innovative treatment strategies and the improvement of prognosis of SIC.
Guoxia Zhang, Hong-shuang Liu, Qing Zhang et al.· Frontiers in Pharmacology· 0 citations
Diabetes mellitus is a global health burden recognized by progressive microvascular complications, which comprise diabetic retinopathy, nephropathy, and neuropathy, often known as diabetic triopathy. Despite extensive research, the mechanistic convergence of multi-organ damage is not fully understood. Recent studies highlighted that ferroptosis, an iron-dependent form of regulated cell death mediated by lipid peroxidation, plays a crucial role in diabetic tissue damage. Importantly, mitochondria are key modulators of ferroptotic susceptibility because they regulate reactive oxygen species (ROS) production, iron homeostasis, and bioenergetic homeostasis. This review proposes mitochondrial-ferroptotic crosstalk as a unifying mechanistic axis associating retinal, renal, and neural complications in diabetes. We present a comprehensive overview of the molecular basis of ferroptosis through a mitochondria-centered perspective, covering key pathways such as iron homeostasis, the glutathione-GPX4 system, and emerging regulators of ferroptosis such as SLC7A11 and the FSP1-coenzyme Q axis. We also discuss shared vulnerabilities across microvascular tissues, such as mitochondrial dysfunction, iron overload, lipid peroxidation, and chronic inflammation. Tissue-specific evidence supporting ferroptosis in diabetic retinopathy, nephropathy, and neuropathy is discussed critically, with with mitochondrial impairment and redox imbalance emerging as prevalent drivers of the pathophysiology. Finally, we assess current and novel therapeutic approaches targeting the mitochondrial-ferroptotic axis, such as ferroptosis inhibitors, mitochondrial antioxidants, and iron-regulating approaches. Altogether, this integrative model identifies mitochondrial-ferroptotic crosstalk as a key pathogenic mechanism and therapeutic opportunity to mitigate multi-organ complications in diabetes.
Satyam Yadav, Issac V. Cherian, Akansha Sharma et al.· Mitochondrion (Amsterdam. Pr...· 0 citations
Abstract Sepsis is a life-threatening organ dysfunction driven by a dysregulated host response to infection, yet targeted pharmacological therapies remain severely limited. Emerging evidence highlights ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, as a pivotal mechanism underlying sepsis pathogenesis and subsequent multiple organ dysfunction syndrome (MODS). While the pathological relevance of ferroptosis is well-established, comprehensive reviews exploring the potential of Traditional Chinese Medicine (TCM) and natural bioactive compounds to therapeutically modulate this pathway in sepsis remain scarce. This review systematically evaluates diverse TCM-derived phytochemicals, including flavonoids, terpenoids, alkaloids, and polyphenols, elucidating their molecular mechanisms in attenuating sepsis-induced ferroptosis. Specifically, we detail how these natural products mitigate multi-organ injury by restoring iron homeostasis, quenching lipid peroxidation cascades, and upregulating core antioxidant axes, notably the Nrf2/SLC7A11/GPX4 signaling pathway. By synthesizing current preclinical evidence encompassing isolated bioactive compounds and classical TCM formulae, this review aims to clarify the pharmacological rationale of TCM in sepsis management, offering novel insights for the discovery of innovative therapeutic targets and the development of precision medicine strategies.
Fan Wu, Changlan Gao, Xiangru Zheng et al.· Journal of Inflammation Rese...· 0 citations
Diabetic cardiomyopathy (DCM) is a major complication of type 1 diabetes mellitus (T1DM) with limited treatment options. Dyrk1a is involved in multiple diseases, comprising neurodegenerative disorders, cancer and diabetes. In addition, Dyrk1a is an emerging therapeutic target. Nonetheless, it remains ambiguous with regard to its role in T1DM-related DCM. The present study investigated the function and mechanisms of Dyrk1a in DCM. Experimental T1DM was induced through sequential low-dose streptozotocin administrations via intraperitoneal delivery. The investigation showed conspicuous cardiac upregulation of Dyrk1a protein expression in this T1DM murine model. Pharmacological intervention was performed by employing the Dyrk1a-targeting compound harmine, administered through oral gavage, which ameliorated cardiac dysfunction characteristic of DCM. This therapeutic efficacy was mechanistically linked to ferroptosis inhibition, which was established through harmine-mediated attenuation of pathological signatures, namely reduced malondialdehyde accumulation, enhanced glutathione bioavailability, as well as elevated expression of ferroptosis regulators SLC7A11 and GPX4. It is noteworthy that co-administration of the ferroptosis activator erastin nullified the cardioprotective properties of harmine. Together, these findings establish harmine as an effective modulator of ferroptosis pathways, conferring protection against hyperglycemia-induced cardiomyocyte injury. Dyrk1a inhibition enhances cardiac function in T1DM by reducing ferroptosis.
Junjian Chen, Wanyi Zhang, Tao Hong et al.· Molecular Medicine Reports· 0 citations
Evidence showing that TFAM upregulation, whether through pharmacological interventions or genetic manipulation, consistently protects against tubular cell injury, preserves mitochondrial function, and attenuates inflammation across diverse AKI models is integrated.
Metabolic dysfunction-associated steatotic liver disease has emerged as the most prevalent liver disease with a rapidly increasing incidence worldwide. Targeting mitochondria in this condition opens up innovative avenues for the development of new therapeutic molecules. Mitochondrial dysfunction potentially influences the pathways of this disease and facilitates lipid accumulation and inflammation in hepatocytes, which can be targeted and reversed in the liver. Mitochondria are crucial in signalling pathways that regulates oxidative stress and fatty acid are essential for maintaining the integrity of hepatocyte. Mitochondrial dysfunction significantly influences the onset and progression of metabolic dysfunction-associated steatotic liver disease, revitalising the research of steatotic liver therapy. The limited availability of treatment strategies arises from the heterogeneity of the disease pathology, and for a considerable time, insights into the aetiology of the disease remained unclear. Until very recently, treatment options for managing the condition were limited to antidiabetic, anti-inflammatory, and miscellaneous drugs. However, Resmetirom has emerged as the only FDA-approved drug, that specifically targets the thyroid hormone receptor-β receptor in the liver. More direct and targeted therapies are essential for this condition. Targeting the mitochondrial dysfunction significantly expands the landscape of therapeutic potential, facilitating the introduction of additional therapies aimed at preventing, managing, or curing the condition, alongside the traditional therapies currently available.
