Peritoneal dialysis (PD) is one of the main measures of alternative therapy for end-stage renal disease (ESRD). In recent years, with the optimization of PD technology and materials, the improvement of patients' understanding of PD, and the continuous improvement of PD support and management by medical insurance policies, China has experiences one of the most significant increases in the utilization rate of PD (Anumudu et al., 2021; Li et al., 2017). Unfortunately, with the increase in patients' dialysis age, a variety of pathological factors led to peritoneal injury, peritoneal structure remodeling, and peritoneal fibrosis (PF), which gradually reduced the dialysis efficiency and led to the withdrawal of PD treatment (Teitelbaum, 2021).

The PMC monolayer is the initial barrier against extrinsic damage factors and is able to preserve the peritoneum's structural and functional integrity (Strippoli et al., 2016). PMCs are not only passive victims of peritoneal injury but have also been shown to be active participants in the PF development (Liu et al., 2015). PMCs with a myofibroblast phenotype are more aggressive and have the ability to secrete extracellular matrix (ECM). Therefore, mesothelial-mesenchymal transition (MMT), as a key pathological process in the early stage of PF, has been a research hotspot in the field of PF. TGF-β1 is the core factor mediating PMCs MMT, which can be divided into two modes: SMAD-dependent and non-SMAD-dependent signal transduction (Hu et al., 2018). Increased expression of Wnt and β-catenin proteins was detected in PMCs isolated from dialysis effluents of PD patients. Improvements in PMCs MMT after treatment with β-catenin inhibitors imply a role for the Wnt/β-catenin signaling pathway in PF (Ji et al., 2017). By evaluating the single-cell transcriptomes of PMCs obtained from normal peritoneal biopsies as well as from the abdominal effluents of PD patients, glycolysis was discovered to be intimately associated with PMCs MMT development (Si et al., 2019). This abnormal metabolic state can be corrected by regulating peritoneal microRNA, which can block glycolysis and inhibit TGF-β1-induced PMCs MMT and peritoneal fibrosis pathological changes in mice (Li et al., 2019; Wu et al., 2019). These results suggest that PMCs MMT is an important cause of PD-related PF.

The perennial herb Centella asiatica (L.) Urb., which belongs to the Apiaceae (Umbelliferae) family, is extensively distributed in China, India, Japan, and other countries. It also known as "Luode Da", "Bang Da Wan" and "Ban Bian Qian", and was first recorded in the Shen Nong's Classic of Materia Medica. With the traditional effects of clearing away heat and dampness, detoxifying and detumescence, it can be used for various damp heat syndrome and swollen toxin syndrome through syndrome differentiation, including skin diseases, gastrointestinal diseases, immune diseases, inflammatory diseases, and fibrotic diseases (Sun et al., 2020). ASI is the main component of Centella asiatica, with variety of pharmacological effects and low toxicity (He et al., 2022). In vivo studies have confirmed that ASI can attenuate bleomycin-induced pulmonary fibrosis by promoting A2AR expression and activating the BMP7/Smad1/5 signaling pathway (Luo et al., 2020; Zhang et al., 2020). In a 5/6 nephrectomy mouse model, ASI can upregulate BMP-7 and E-cadherin, downregulate the expression of fibrosis genes such as Vimentin, and reduce renal interstitial fibrosis and renal tubular injury (Arfian et al., 2019). These results suggest that ASI can prevent and treat various tissue fibrosis diseases through multitarget synergistic action. Our research team has accumulated some experience in the application of ASI in PD-related PF. In vitro studies have confirmed the presence of HPMCs MMT during PF, and TGF-β1 activates MMT by phosphorylating Smad2/3 in HPMCs. However, this effect can be blocked by ASI and TGF-βR inhibitors. Additional investigations have shown that ASI can enhance PMC apoptosis by suppressing ROS formation, irrespective of the TGF-β/Smad signaling pathway, indicating that ASI is a multitarget agent with anti-ROS and anti-MMT properties.

To investigate further the molecular mechanism by which ASI inhibits PMCs MMT, proteomics analysis combined with network pharmacology analysis were used in this work to obtain the differential proteins expression in the process of PF and predict the core target genes and potential anti-PF molecular mechanism of ASI.