Acute Kidney Injury (AKI) is a common and serious clinical condition characterized by a sudden decrease in renal excretory function accompanied by elevated serum creatinine (CREA) levels and reduced urine output [1]. It has a high clinical incidence and serious and poor prognosis [2]. Untreated AKI can progress repeatedly to chronic kidney disease or renal failure [3]. However, clinical treatment options for AKI remain limited, primarily focusing on symptomatic treatments [4] such as vasodilators, diuretics, or dialysis [5]. TCM offers a promising avenue for research in the quest for more effective treatments for AKI. The Chinese herb Fuzi, the daughter root of Aconitum carmichaelii Debx, has long been used to treat kidney diseases [6], [7]. Within Aconitum plants, the core active compounds, known as aconitine alkaloids, are of great interest [8] and have demonstrated potential pharmacological activities in various domains, including anti-inflammatory, anticancer, immunomodulatory, and cardiovascular-protective effects [6], [8], [9], [10].

Mesaconine, an ester-free alkaloid from Fuzi, is speculated to have potential nephroprotective effects owing to its unique structure, excellent pharmaceutical activity, and low toxicity compared to double ester alkaloids [11]. Despite the use of mesaconine in heart disease study [12], there is limited detailed research available in the existing literature regarding the use of mesaconine in improving AKI, making its potential therapeutic effects and mechanisms an area that requires further investigation.

In clinical applications, certain chemicals are frequently employed to induce models of Acute Kidney Injury (AKI) owing to their unavoidable side effects and well-established nephrotoxic properties. These include aminoglycoside antibiotics, cisplatin, glycerol, folic acid, and contrast agents [13]. Gentamicin (GM), an aminoglycoside antibiotic, induces dose-dependent nephrotoxicity, which is primarily linked to its accumulation in the proximal tubules of the kidney [14]. Several factors contribute to GM-induced AKI, including mitochondrial dysfunction [15], oxidative stress, activation of the NF-κB inflammatory pathway, and apoptosis or necrosis of renal tubular cells [16]. Mitochondrial dysfunction is one of the earliest indicators of GM-induced nephrotoxicity and plays a central role in the pathogenesis of AKI [17]. During mitochondrial energy production, the mitochondrial respiratory chain generates reactive oxygen species (ROS) [18], typically neutralized by the intracellular antioxidant defense system. However, during AKI, the mitochondrial respiratory chain in renal tubular cells is compromised, resulting in increased mitochondrial damage that cannot be efficiently cleared [19]. This leads to the onset of oxidative stress, triggering an intracellular inflammatory response that culminates in apoptosis via the mitochondrial pathway [20].

Considering the pivotal role of mitochondrial dysfunction in AKI development and the potential anti-AKI properties of mesaconine, we postulated that mesaconine might hold therapeutic promise for AKI. We proposed that mesaconine ameliorates mitochondrial dysfunction, thereby inhibiting downstream oxidative stress, inflammation, and apoptosis. Consequently, we conducted a comprehensive investigation of the effects of mesaconine on NRK-52E cells and rats following GM stimulation. Our study aimed to elucidate the potential mechanisms underlying the therapeutic effects of mesaconine in AKI.