Acute kidney disease (AKI) is a syndrome with high mortality, characterized by abrupt loss of kidney function within hours. Approximately 10–15% of hospitalized patients have AKI as a complicating factor, and in the ICU the percentage can reach more than 50% (Pickkers et al., 2021; Zuk and Bonventre, 2016). AKI has many causes, among which drug-induced AKI is relatively common in hospitalized patients. Cisplatin, a first-generation chemotherapeutic drug, has been used for thirty years to treat numerous tumors, such as bladder, lung, and ovarian cancers (Miller et al., 2010; Oun et al., 2018). However, its clinical use is hindered by its side effects on the alimentary canal, liver, kidney, nervous system, hearing, and blood system. Renal toxicity is the main dose-limiting side effect. With an intravenous infusion of cisplatin (50–100 mg/m2), at least 30% of patients develop nephrotoxicity and are at a higher risk for AKI(Volarevic et al., 2019). The main approaches against cisplatin-induced nephrotoxicity in the clinic include hydration, supplementation with magnesium, or application of mannitol to induce forced diuresis(Crona et al., 2017). However, mannitol treatment may cause over-diuresis and dehydration. Hence, there is a considerable need to further elucidate the pathogenesis underlying cisplatin toxicity and develop safe and effective therapeutic strategies.

After cisplatin administration, 90% of the drug is cleared through the kidneys. Transporters localized in the proximal tubules, such as OCT2, CTR1, and MATE1, mediate the uptake and excretion of cisplatin (Estrela et al., 2017; Harrach and Ciarimboli, 2015). Consequently, cisplatin accumulates in the tubular segment and induces many intracellular stresses, including oxidative stress, endoplasmic reticulum stress, and mitochondrial stress. Cisplatin also causes multiple tissue-level stress responses, including cell-cycle arrest, cell death and excessive inflammation in the kidney(Mcsweeney et al., 2021). To date, various approaches have been identified to relieve cisplatin nephrotoxicity, but there is still a long way to go for clinical application and further studies are needed. Inflammation and apoptosis are important features of cisplatin-induced AKI, and contribute to maladaptive repair. Thus, resolution of inflammation and apoptosis may be an effective approach for treating AKI.

The cGAS/STING pathway plays a pivotal role in the innate immunity (Jiang et al., 2020; Sun and Hornung, 2022). cGAS, an intracellular pattern recognition receptor and cytosolic DNA sensor, recognizes exogenous and endogenous DNA localized in the cytosol. Following activation by DNA, cGAS synthesizes cGAMP from GTP or ATP. The cGAMP binds to STING and drives its translocation to the Golgi apparatus. The STING carboxyl terminus recruits and activates TBK1 and phosphorylates IRF3. IRF3 enters the nucleus to introduce type I interferons and the transcription of pro-inflammatory molecules (Hopfner and Hornung, 2020; Zierhut et al., 2019).In addition, cGAMP can transactivate STING in adjacent cells(Chen et al., 2016) through junction proteins to amplify the inflammatory response(Pépin et al., 2020). cGAS/STING activation serves as an important defense against infection. However, abnormal and systemic activation of STING can lead to autoimmune diseases (Decout et al., 2021; Paul et al., 2021). Also, excess and prolonged cGAS/STING pathway activation can exacerbate renal pathological injury in chronic kidney disease (CKD) (Chung et al., 2019; Ma et al., 2022). Therefore, targeting cGAS and STING could be a significant therapeutic strategy to alleviate cisplatin-induced AKI.

Traditional Chinese medicines are widely used to prevent and treat renal disease. According to traditional Chinese medicine theory, cisplatin-induced AKI is caused by the drug's toxicity, or by oedema. Qi deficiency of the kidney and spleen, dampness, and blood stasis syndrome are the main pathologies of cisplatin-induced AKI. YSXZF was developed from the classic prescriptions Mulizexie powder and Buyanghuanwu Decoction. Mulizexie powder is documented in the book of Golden Chamber Synopsis as having the effects of eliminating water from the body and reducing swelling. Buyanghuanwu Decoction is recorded in the book of Correction of Errors in Medical Classics as tonifying qi, activating blood, and opening the collateral vessels. The YSXZF mixture comprises four herbs: Astragali Radix (Huangqi), Alismatis Rhizoma (Zexie), Paeoniae Radix Rubra (Chishao), Sargassum (Haizao). Huangqi is the “monarch” herb that can tonify qi, eliminate water from the body, reduce swelling and remove toxins. Zexie and Chishao are “minister” herbs, of which Zexie can eliminate water from the body, reduce dampness and transform turbidity, and Chishao can improve blood stasis. Haizao, the “adjuvant” herb, can soften hardness, dissipate bonds, and assist Zexie in eliminating water and reducing swelling. The four herbs work together to tonify the qi of the spleen and kidney, improve blood stasis and relieve turbidity. YSXZF, as a simplified clinical experience prescription of the famous Guangdong Province clinical expert Professor Luo Ren, has been used in our hospital for years to treat CKD (H. Liu et al., 2019; Ji et al., 2017). Many of these herbs, their extracts, and isolated compounds have therapeutic effects in renal disease (Feng et al., 2014; Josephine et al., 2007; X. Liu et al., 2019; Murata et al., 2017). However, the components, targets, and pathways influenced by traditional Chinese medicine prescriptions are always complex. Exploring the effects of YSXZF in AKI and elucidating the underlying mechanisms could provide a scientific foundation for its clinical application and promotion.

Therefore, this study aimed to explore the effectiveness of YSXZF in restoring renal function and in alleviating pathology in a cisplatin-induced AKI mouse model, and to investigate the effects of YSXZF on cell apoptosis and inflammation. Moreover, we aimed to identify the major components in serum after YSXZF administration, using ultra-high pressure liquid chromatography-mass spectrometry (UHPLC-MS).