Doxorubicin (DOX) has been recognized as one of the most effective chemotherapies and extensively used in the clinical settings of human cancer. However, DOX-mediated cardiotoxicity is known to compromise the clinical effectiveness of chemotherapy, resulting in cardiomyopathy and heart failure. Recently, accumulation of dysfunctional mitochondria via alteration of the mitochondrial fission/fusion dynamic processes has been identified as a potential mechanism underlying DOX cardiotoxicity. DOX-induced excessive fission in conjunction with impaired fusion could severely promote mitochondrial fragmentation and cardiomyocyte death, while modulation of mitochondrial dynamic proteins using either fission inhibitors (e.g., Mdivi-1) or fusion promoters (e.g., M1) can provide cardioprotection against DOX-induced cardiotoxicity. In this review, we focus particularly on the roles of mitochondrial dynamic pathways and the current advanced therapies in mitochondrial dynamics-targeted anti-cardiotoxicity of DOX. This review summarizes all the novel insights into the development of anti-cardiotoxic effects of DOX via the targeting of mitochondrial dynamic pathways, thereby encouraging and guiding future clinical investigations to focus on the potential application of mitochondrial dynamic modulators in the setting of DOX-induced cardiotoxicity.

The clinical use of doxorubicin (DOX), an effective chemotherapeutic drug for breast cancer, is limited by off-target nephrotoxicity, which is exacerbated in elderly patients. While excessive mitochondrial fission is known to contribute to DOX-induced cardiotoxicity, its role in DOX-induced nephrotoxicity, particularly in the context of renal aging, remains unclear. To explore this and investigate the therapeutic potential of the mitochondrial fission inhibitor Mdivi-1, female Wistar rats with D-galactose-induced accelerated renal aging were allocated into four groups: vehicle, DOX, DOX+Mdivi-1 co-treatment, and DOX+Mdivi-1 post-treatment. DOX administration resulted in significant renal dysfunction, oxidative stress, inflammation, and histopathological damage. Mitochondrial dysfunction along with the increased expression of fission protein, decreased fusion proteins, and activation of apoptotic markers and PINK1 expression were also evident. Remarkably, both co-treatment and post-treatment with Mdivi-1 comparably and significantly attenuated DOX-induced renal damage. This study suggests that Mdivi-1 mitigates DOX-induced nephrotoxicity in the aged kidney by modulating mitochondrial dynamics, suppressing oxidative stress and inflammation, and inhibiting apoptosis. These findings highlight mitochondrial fission as a promising therapeutic target for the treatment of doxorubicin toxicity and provide further support for the possible use of Mdivi-1 as a therapeutic strategy to protect the kidneys of elderly breast cancer patients undergoing chemotherapy.

Chronic myocardial infarction (CMI) is a leading cause of heart failure and is increasingly recognized as a systemic condition involving multi-organ dysfunction, particularly impaired gut health due to systemic inflammation and metabolic disturbances. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, exerts cardioprotective effects beyond glycemic control, but its role in CMI-induced gut dysbiosis and barrier dysfunction remains unclear. This study aimed to determine whether dapagliflozin mitigates CMI-induced gut dysbiosis and intestinal barrier dysfunction—alongside systemic inflammation and metabolic disturbances—and whether these changes are associated with improved cardiac function. Thirty-nine male Wistar rats underwent left anterior descending (LAD) coronary artery ligation (CMI, n=26) or sham surgery (n=13). One-week post-surgery, CMI rats with anterior wall akinesia and left ventricular ejection fraction (LVEF) <50% were randomized to receive vehicle (distilled water; n=13) or dapagliflozin (1 mg/kg/day, oral; n=13) for 10 weeks. Outcomes measured included cardiac function, gut microbiota composition, gut barrier integrity, intestinal apoptosis, inflammatory cytokines, and levels of plasma microbial metabolites—short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO). Dapagliflozin improved cardiac function and attenuated CMI-induced gut dysbiosis by restoring microbial diversity, enriching beneficial bacteria (UCG-007, Bacillus), and reducing harmful taxa (Holdemania). Gut barrier integrity was preserved through upregulation of tight junction proteins (TJPs) and suppression of intestinal apoptosis and inflammation. Metabolically, dapagliflozin increased butyrate production while lowering plasma TMAO levels, indicating a favorable microbial metabolic shift. In this CMI rat model, dapagliflozin was associated with changes in the gut-heart axis that may relate to its observed cardioprotective effects. Further studies are required to determine causality and the relative contribution of these pathways.

Background: Myeloid differentiation factor 2 inhibitor (MD2i) is a novel anti-inflammatory agent that exerts favorable outcomes in various diseases including cardiac ischemia/reperfusion (I/R) injury. However, whether a potent antioxidant N-acetyl cysteine (NAC) can augment the beneficial effects of MD2i in rats with cardiac I/R injury have never been investigated. Purpose: We tested the hypothesis that NAC increases the beneficial effects of MD2i against cardiac I/R injury in rats. Methods: Rats were divided into either a sham (n=6) or cardiac I/R group (n=72). Rats in the I/R group received one of the following 6 treatments (n=12 each) at the onset of reperfusion: vehicle, MD2i at 20 and 40 mg/kg, NAC at 75 and 150 mg/kg, and combined MD2i 20 mg/kg with NAC 150 mg/kg. Left ventricular (LV) function, infarct size, arrhythmia score, and cardiac mitochondrial function and dynamics were determined. Results: Myocardial infarction, LV dysfunction, and cardiac arrhythmias were observed in rats with cardiac I/R injury, along with mitochondrial dysfunction (Fig. 1). Treatment with MD2i at either 20 or 40 mg/kg effectively reduced LV dysfunction but failed to reduce the infarct size (Fig. 1). NAC at 150 mg/kg, but not at 75 mg/kg, significantly decreased both LV dysfunction and infarct size following cardiac I/R injury (Fig. 1). However, combined treatment exerted even greater efficacy in reducing cardiac I/R injury than monotherapy, through a greater reduction of cardiac mitochondrial dysfunction and mitochondrial fission (Fig. 1). However, no benefit on reducing the arrhythmia score in all groups. Conclusion: Combined MD2i and NAC treatment exerted a superior cardioprotective effect against cardiac I/R injury than either monotherapy regimen via an improved cardiac mitochondrial function. Funding Acknowledgement: Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1. NSTDA Research Chair Grant from the National Science and Technology Development Agency Thailand2. National Research Council of Thailand