Baicalin itself cannot be directly absorbed by the intestinal tract and is first hydrolyzed by intestinal bacteria to its glycoside baicalein (Akao et al., 2000). Using the in situ absorption approach, a preliminary assessment of the absorption sites of baicalin in rats’ stomachs and various intestine segments revealed two distinct sites of absorption in one research. Baicalin was absorbed in two different ways: first, it was absorbed in the upper intestine, probably directly; and second, it was absorbed as glycosides in the colon (Lu et al., 2007). One of the most significant techniques for researching medication absorption in rats is in situ perfusion. In a rat study, the authors performed in situ perfusion in rats with and without ligated bile ducts, and the experiments’ findings from 2006 demonstrated that baicalin absorbed badly in the small intestine and colon and somewhat in the stomach, suggesting that baicalin was unable to effectively pass through the intestinal epithelium (Taiming and Xuehua, 2006).

Baicalin can accumulate in various tissues. The largest quantity of baicalin was detected in the kidneys, and the drug’s subsequent concentration in each of the main organs in the following order: kidneys > lungs > liver > spleen, according to a tissue distribution study conducted after injection. Following an intravenous injection of liposomal baicalin, the lungs exhibited the highest concentration of the medication. Subsequently, the concentration of the drug declined in the following sequence in the major organs and tissues: kidney > spleen > liver > lungs (Wei et al., 2016). Another finding was that baicalin in the preparation of Huanglian Xieyu Tang was rapidly distributed in the lungs and accumulated at high levels in the lungs (Zhu et al., 2013). In the kidney, the distribution of scutellarin and its metabolite scutellarein isolated from Scutellaria baicalensis showed that the two were mainly distributed in the renal cortex and medullary regions with high abundance, suggesting that scutellarin may have the potential to prevent and treat kidney diseases (Wang T. et al., 2021).

With regard to gastrointestinal hydrolysis, enterohepatic circulation, carrier-mediated transport, and complex metabolism, baicalin possesses a distinct pharmacokinetic profile. Once baicalin is absorbed, the interaction between baicalin and its aglycone baicalein will occur in the body. Studies in rats have demonstrated that baicalin is rapidly converted to baicalein in the gut through the enzymatic activity of β-glucuronidase, a process contingent upon the presence of gut microbiota. Then, once baicalin enters the systemic circulation, it is converted back to baicalein by Uridine diphosphate glucuronosyltransferase (UGT) (Akao et al., 2000; Noh et al., 2016). 18.7% of the baicalin that was administered orally entered the enterohepatic circulation. These findings demonstrate that a substantial amount of baicalin is subjected to first-pass glucuronidation and that the enterohepatic circulation significantly influences the amount of baicalin that is exposed to rats (Xing et al., 2005a). Wistar rats’ plasma contained baicalein 6-O-β-dlucopyranuronoside (B6G) as the major metabolite after oral baicalin treatment at 20 mg/kg of dosage, and its level was greater than that of baicalin (Akao et al., 2013). Furthermore, the existence of baicalin isomers in plasma following oral treatment suggests that baicalin is at least partially converted to baicalein prior to absorption and then to its conjugated metabolite in rats (Xing et al., 2005b). In recent years, in order to obtain more metabolites, the metabolites of baicalin were studied by linear ion trap-orbitrap mass spectrometry, and 32 metabolites in all were found and described. Also, The corresponding reactions of baicalin in vivo were also found, such as methylation, methoxylation, hydrolysis, hydroxylation, glucuronic acid binding, sulfate binding and complex reactions (Zhang et al., 2015), indicating that baicalin has a complicated metabolism and that these isomers could greatly enhance baicalin’s benefits if they have biological activity.

In the body, baicalin is first absorbed as baicalein and subsequently converted to baicalin. It is possible for the colon to excrete some of the baicalein that is generated from absorbed or intravenously administered baicalein (Taiming and Xuehua, 2006). Meanwhile, in a previous study, using the in situ jejunal loop technique and in vitro jejunal ectopic capsule assay, It was shown that multidrug resistance binding protein 2 (MRP2) significantly processed baicalein in intestinal mucosal cells to produce baicalin, which was then eliminated into the intestinal lumen (Akao et al., 2004). It is important to note that rats and humans dispose of baicalin quite differently. Notably, the UGT activity of rat jejunum microsomes against baicalin is comparable to that of liver microsomes, even though the liver is traditionally regarded as the primary site for xenobiotic metabolism (Akao et al., 2004). Furthermore, an in vitro absorption experiment utilizing everted rat jejunal sacs revealed that baicalin emerged outside the sac rather than inside it, whereas very little of the baicalein absorbed was transported to the inner (serosal) side of the sac. Eisai hyperbilirubinemia rats (EHBR) with hereditary MRP2 deficiency exhibited a considerably decreased jejunal sac effection rate (56.4%) in comparison to wild-type Sprague-Dawley rats, indicating that baicalin efflux may be mediated by MRP2. The human colonic adenocarcinoma cell line Caco-2 is used to study the absorption and disposition of drugs in the human gut, although it is limited in the expression of certain transporters and metabolic enzymes. Baicalein can be transported bidirectionally (from the apex to the basal side and from the basal side to the apex) in a single-layer model of Caco-2 cells, while the levels of the glucuronides formed are very low (Ng et al., 2004). In addition, baicalin was mainly accumulated on the basal side, suggesting that MRP3 may be involved in baicalin transport (Zhang et al., 2005). Furthermore, research has demonstrated that the primary transport medium for the body’s absorption and utilization of flavonoids (including baicalin, catechin, quercetin, etc.) is human serum albumin (HSA). The degree to which baicalin binds to human serum albumin determines its transit rate and volume distribution inside the host. Specifically, the relative absorption rate of baicalin is approximately 65%, as indicated by the area under the time-concentration curve (AUC _∞ ) (Wen et al., 2023). This difference may be related to differences in intestinal flora composition, metabolic enzyme activity, and transporter expression between humans and rats, which together affect drug absorption and metabolism processes. It has also been reported that enzymes in the digestive tract (e.g., β-glucosidase or lactase chlorin hydrolase (LPH) are involved in the hydrolysis of flavonoids, which suggests to us that this enzyme may be involved in the hydrolysis of baicalin (Murota et al., 2018). A study that included ten healthy male volunteers also discovered that baicalin was recovered from urine at doses of 5.0, 10.0, and 20.0 mg/mL, with baicalin recoveries from urine of 105.9%, 101.1%, and 108.4%, respectively, after oral administration of the drug. Correspondingly. Baicalin was recovered in 105.9%, 101.1%, and 108.4% of the urine samples, suggesting that urine is another route by which baicalin can be eliminated (Lai et al., 2003).

The physiological process of inflammation serves to shield the body against acutely harmful stimuli like ischemia, poisons, or viruses, and plays a defensive role in injury or infection (Saade et al., 2021). Inflammation is closely related to AKI, an inflammatory state can cause AKI, which in turn can exacerbate the inflammatory response. Indeed, a number of ischemia, toxic, or immune disorders can harm renal cells by causing inflammation and cell death, which subsequently damages other organs and ultimately results in total failure (Feng Q. et al., 2022). Pro-inflammatory cytokines, chemokines, adhesion molecules, different growth factors, and nuclear factors are some of the molecular characteristics of inflammation that are linked to the inflammatory response. Minimizing the detrimental effects of cytokines on the kidneys is crucial since the decline in renal function during AKI typically causes cytokine concentrations to rise in tandem with a decrease in plasma cytokine clearance (Andres-Hernando et al., 2012). AKI trauma patients had much greater levels of IL-1, IL-8, IL-6 and MCP-1 early in life compared to trauma patients without AKI (Ma et al., 2021). Inflammatory mediators such as inflammatory factors (TNF-α, TGF-β, IL-6, IL-1β, IL-18), chemokines (CCL2), and adhesion factors (ICAM-1,MCP-1 and P-selectin) are induced when kidney injury occurs, which facilitates the recruitment of leukocytes to the kidney and the arrival of macrophages, neutrophils, and lymphocytes at the site of injury (McWilliam et al., 2021). According to recent research, TNF-α, IL-6, and IL-1β have been found to be significant participants in the pathogenesis of renal injury (Ramesh and Reeves, 2002). And inhibition of these inflammatory cytokines attenuates renal tissue damage. Therefore, early anti-inflammatory treatment can improve renal function. By inhibiting the manufacture of inflammatory factors and preventing the inflammatory pathway, baicalin can provide protection against AKI. As evidenced by a notable decrease in IL-10 levels and a considerable increase in TNF-α, IL-8, and IL-6 levels in renal tissue, cisplatin was found to induce a strong pro-inflammatory response in rat renal tissue in one investigation (Kumar et al., 2017). And in several studies, Baicalin demonstrated its ability to suppress ROS release, which raised oxidative stress in cells, released more malondialdehyde (MDA) and superoxide dismutase (SOD), and reduced TNF-α, IL-6, IL-8, and IL-1β levels (Li et al., 2022; Liao et al., 2016; Lim et al., 2012). Academic circles largely recognize the nuclear transcription factor κB (NF-κB) pathway as a significant pro-inflammatory signaling pathway, mostly because of NF-κB’s critical function in controlling the expression of pro-inflammatory genes such adhesion molecules, cytokines, and chemokines (Lawrence, 2009). By coordinating inflammatory processes that aid in the onset and progression of AKI, NF-κB plays a essential role in the pathophysiology of the condition (Liu and Dong, 2021). NF-κB binds to IκB protein in an inactivated state under normal conditions. When cells are stimulated internally and externally, activation of proximal signal bridging proteins leads to activation of IκB kinase and degradation of IκB proteins by phosphorylation ubiquitination, and thus NF-κB is released, translocated to the nucleus and binds to particular target genes, initiating transcription of the target genes and further inducing an acute inflammatory response. The activation of classical NF-κB causes the active immune system to create pro-inflammatory cytokines, which in turn trigger an inflammatory response (Oeckinghaus et al., 2011). Conversely, these pro-inflammatory cytokines activate classical NF-κB (Yu et al., 2020). This leads to a vicious circle. Studies have shown that baicalin significantly reduced the number of CD68⁺ macrophages and CD3⁺ lymphocytes, in addition to affecting NF-κB signaling by downregulating IκB expression and upregulating TNF-α, NLRP3 and P65 expression (Zhang X. T. et al., 2020). Baicalin inhibits the TLR4/MyD88/NF-κB signaling cascade in an ischemia-reperfusion injury (IRI) model, hence reducing the synthesis of pro-inflammatory proteins brought on by renal ischemia-reperfusion injury (IRI). Furthermore, it suppresses apoptosis by reducing cleaved caspase-9 levels (Lin et al., 2014a). An essential component of the innate immune system, the NLRP3 inflammasome promotes caspase-1 activation and the release of pro-inflammatory cytokines, such as IL-1β and IL-18, in response to microbial infections and cellular injury (Kelley et al., 2019). In cisplatin-induced AKI (CI-AKI) models that are both in vivo and in vitro, renal damage and apoptosis have been shown to be aggravated by the activation of the NLRP3 inflammasome and the ensuing generation of IL-1β and IL-18 (Shen et al., 2016; Lin et al., 2019). In contrast, following baicalin therapy, the pro-inflammatory factors IL-1β and IL-18 as well as the amount of active caspase-1 were reduced due to the inhibition of NLRP3 inflammasome activation (Li et al., 2022; Sun et al., 2020). In conclusion, baicalin has a potent anti-inflammatory action that may prevent AKI by lowering immune cell activation and infiltration as well as the synthesis and release of inflammatory mediators.

An imbalance in the body between oxidation and antioxidants is identified as oxidative stress. The overabundance of ROS is acknowledged as a critical element contributing to the development of oxidative stress. Differential intracellular oxidative stress levels cause intracellular oxidative components to be misregulated, which in turn causes the production of oxidative markers like SOD and MDA, which promotes the process of apoptosis (Hajam et al., 2022). In renal cells, oxidative stress causes a number of harmful outcomes, including DNA damage, lipid peroxidation, protein modification, pro-inflammatory and pro-fibrotic pathway activation, and apoptosis induction (Emma et al., 2016). A range of antioxidant defense mechanisms exist within cells for scavenging free radicals and maintaining oxidation-reduction balance. These include antioxidant enzymes (e.g., SOD, GSH) and non-enzymatic antioxidant substances (e.g., glutathione, vitamin C, vitamin E, etc.). Research has indicated a significant correlation between oxidative stress and AKI. The aetiology of increased oxidative stress and consequent ischemic renal cell injury is linked to the direct nephrotoxic effects of contrast agents and cisplatin on renal tubular epithelial cells as well as the physiological alterations brought on by the release of vasoactive molecules (Chandiramani et al., 2020; Holditch et al., 2019). ROS disrupt a variety of signaling pathways, such as PI3K, MAPK, Nrf2, iron metabolism, and cell death, if they are not properly neutralized and strong antioxidant baicalin controls oxidative stress in cells through both direct and indirect means, including scavenging ROS and raising the activity of antioxidant enzymes, which prevents AKI (Li et al., 2022; Lin et al., 2014b). Large-scale production of ROS in the AKI model causes direct oxidative damage to the lipids and proteins in the mitochondria, which reduces the permeability of the mitochondrial membrane by interfering with electron transfer chain (ETC) function and raising mitochondrial bioenergetics (Zhao et al., 2021). Significantly reduced lipid peroxidation MDA increased superoxide dismutase SOD levels after baicalin treatment (Lin et al., 2014a; Zhang et al., 2017). In contrast-induced AKI, it also showed strong antioxidant effects, including lowering ROS, MDA, and increasing SOD levels (Li et al., 2022). Research has indicated that exposure to lead increases oxidative stress (Lin et al., 2019; Sun et al., 2020) and that SOD, GSH-Px, and MDA are targets of lead (Hsu and Guo, 2002). Exposure to lead affects the levels and activity of antioxidant enzymes, thereby damaging cells and tissues. In addition, mice develop a dose-dependent accumulation of lead, primarily in the kidneys (Yu et al., 2022). In contrast, following baicalin therapy, the baicalin group’s SOD and GSH-Px activity rose, and baicalin dose-dependently reduced the elevated MDA levels. Nrf2, a transcription factor, is typically located in the cytoplasm where it binds to the actin-associated Keap1 protein and undergoes normal degradation. This relationship is broken under oxidative stress circumstances, which leads to the translocation of Nrf2 into the nucleus and the subsequent upregulation of the synthesis of cytoprotective enzymes, including HO-1 and SOD (Li et al., 2020). It is well established that the Nrf2-associated signaling pathway provides protection against acute kidney injury brought on by a variety of circumstances (Wang Z. et al., 2021). In rats with AKI from cardiac surgery, The Nrf2 defense mechanism was significantly activated by baicalin pretreatment, as evidenced by increased kidney levels of Nrf2 and downstream aging inhibitor enzymes (e.g., HO-1) (Shi et al., 2019). This implies that baicalin activates Nrf2 oxidative stress, which impairs the defense mechanism against acute kidney injury caused by cardiac surgery. Thus, baicalin has therapeutic potential to antagonize oxidative stress in AKI of various etiologies.

Given that tubular damage can result in a sharp reduction in renal function, it has been observed that tubular epithelial cells injury in sepsis-associated AKI(SA-AKI) (Zhang et al., 2024). Notably, when renal tubular injury is severe, this damage will be irreversible. Although preventive mechanisms of oxidative stress and apoptosis in renal tubular epithelial cells are essential for the treatment of sepsis-associated AKI, little progress has been made in pharmacologic therapy. Renal tubular epithelial cells undergo necrosis and apoptosis in vivo and in vitro due to a variety of conditions, and this result was shown by cell morphology, apoptotic activation of cysteine asparaginase, and TUNEL assay for DNA damage (Thomas et al., 2022; Ren et al., 2020; Wang et al., 2020). And in several studies, baicalin is able to attenuate apoptosis in renal tubular epithelial cells through several pathways, such as mitochondria-dependent pathway, cell death receptor pathway (Wang Y. et al., 2018; Zhang et al., 2007). The caspase cascade triggers apoptosis in response to different injuries. Cacpase3 serves as the downstream effector in this cascade and initiates apoptosis directly upon activation by various upstream signals. Therefore, caspase3 is considered a key indicator (Yang et al., 2014; Yang et al., 2006). Bax and Bcl-2 are pro-apoptotic and anti-apoptotic proteins, respectively, in the mitochondrial apoptotic pathway. Because of their abnormal expression, the outer mitochondrial membrane becomes more permeable, allowing cytochrome c to pass through the membrane and into the cytoplasm (Spitz and Gavathiotis, 2022). In sepsis model mice, baicalin inhibits apoptosis by regulating Bax and Bcl-2 (Zhu et al., 2016). Cell FLICE like inhibitory protein (c-FLIP) is an apoptosis inhibitory protein that reduces lipopolysaccharide-mediated apoptosis in endothelial cells (Shen et al., 2017; Jang et al., 2017). Upon binding to FADD, the activation and recruitment of caspase-8 are inhibited by c-FLIP, thereby suppressing the cascade activation of downstream caspases and ultimately preventing apoptosis. A study demonstrated that via downregulating the expression of the negative regulator c-FLIP, c-Myc accelerates FasL/Fas-mediated apoptosis in renal tubular epithelial cells (Xu D. et al., 2019). In contrast, baicalin inhibited the apoptosis of renal tubular epithelial cells in SA-AKI mice, thereby considerably protecting the kidneys, and this protective effect may have been caused by enhanced c-FLIP protein expression (Le et al., 2021). Increased organ damage results from IRI, which is the stopping of blood flow to a specific organ and then resuming blood flow and oxygenation. Owing to its unique tissue structure and function, as well as its increased dependence on oxygen delivery, the kidney is especially susceptible to ischemia-reperfusion injury (Van Avondt et al., 2019). In a renal IRI model, baicalin lowered caspase-3 activity and decreased the Bax/Bcl-2 ratio, showing a favorable anti-apoptotic effect, thereby protecting the kidney and attenuating renal pathological changes (Lin et al., 2014a). However, the regulation of apoptotic signaling by baicalin is significantly more complex. For example, in a cellular model of arsenic-induced nephrotoxicity, baicalin elevated the Bcl-2/Bax ratio, thereby protecting the kidney and attenuating renal pathologic changes. The coexistence of necrosis and apoptosis in the pancreas, with necrosis being predominant, may explain why inducing pancreatic apoptosis results in a protective effect.

In AKI, cell death pathways cause necroinflammation (von Mässenhausen et al., 2018). Notably, unlike necrosis, apoptosis does not cause inflammation (Kønig et al., 2019). The term “pyroptosis” was first coined by Cookson and Brennan (2001) to refer to a cysteine-aspartate-specific protease 1 (caspase-1)-dependent cell death pattern. During pyroptosis, NLRP3 binds to the cysteine protease cysteine aspartate proteasome-1 to form inflammasome. Inflammasome can process pre-cysteine aspartyl protease-1 into mature cysteine aspartyl protease-1, leading to inflammatory death of a large number of somatic cells. Thus, “pyroptosis” is inflammatory death (Huang et al., 2021). Previous studies have identified IL-8 and IL-1β as significant markers of pyroptosis. Additionally, the cleavage and activation of the pore-forming effector protein gasdermin D (GSDMD) by activated cysteine asparaginase is a crucial step that triggers pyroptosis, leading to the compromised cells releasing IL-1β and IL-18 (Fu and Wu, 2023; Zhang X. et al., 2020). Apoptosis may result from pro-inflammatory cytokines activating immune cells, creating a detrimental cycle. Research has demonstrated that pyroptosis can be induced by contrast agents via the ROS/NLRP3/Caspase-1/GSDMD pathway, emphasizing baicalin’s capacity to block this mechanism. Intervention with baicalin attenuated the associated inflammation and oxidative levels (Li et al., 2022). Overall, Baicalin exerts an inhibitory influence on renal cell apoptosis by suppressing the activation of apoptotic signaling pathways. This protection shields renal cells from apoptosis triggered by diverse factors.

In AKI, renal pathological changes include tubular injury, interstitial oedema, inflammatory cell infiltration, and more (Huang et al., 2020). Interestingly, baicalin attenuated renal pathological changes and improved renal histopathological scores in several studies, including models of sepsis-induced AKI (Le et al., 2021), or acute pancreatitis-induced AKI (Zhang et al., 2007; Zhang X. P. et al., 2008). For the most effective treatment to be given and additional kidney damage to be prevented, early identification of AKI is essential. In clinical practice, SCr, BUN and urine output are usually considered as the main indicators of renal function. SCr is a product of muscle metabolism, produced by muscle creatine metabolism, and SCr levels are readily available; however, Considering that creatinine concentrations are impacted by muscle mass, proteolytic metabolic rate, age, sex, and race, this is not a suitable marker. In addition, after AKI, SCr is a sluggish surrogate for decreased glomerular filtration rate, and it can take up to 72 h to return to a stable state. BUN is a waste product of protein metabolism, mainly converted from the conversion of amino acids to urea by the liver, both of which are excreted through the kidneys. When the glomerular filtration rate (GFR) decreases, the excretion of these two substances decreases, and the SCr and BUN levels in the blood increase accordingly (Macedo et al., 2011). Urine output and SCr are often the criteria for detecting AKI, but changes in his two are often inconsistent. Nonetheless, they are used as keys to diagnosing AKI (Kellum et al., 2013). A clinical study showed that when urea is reduced in patients with AKI, it reduces mortality (Chávez-Íñiguez et al., 2023). In studies on baicalin, it has been able to restore SCr and BUN to normal levels in multiple causes of AKI models (Wang et al., 2015; Chang et al., 2007). Notably, Clinical trials have demonstrated the considerable impact of baicalin. However, based on the pathogenesis and etiology of AKI, the original renal markers are limited. For example, volume expansion reduces SCr and delays recognition, whereas volume contraction induces an increase in serum concentrations, despite the absence of renal damage (Liu et al., 2011). Acute diseases (e.g., sepsis) and disease complications (e.g., severe malnutrition and sarcopenia) also reduce creatinine production. Neutrophil gelatinase-associated lipid carrier protein (NGAL), which is abundantly expressed and substantially upregulated in the kidney, is thought to be a novel biomarker with a high sensitivity for the detection of AKI (Shang and Wang, 2017). Although multiple renal injury markers can serve as important indicators for the detection of AKI, however, the markers due to different causes of AKI as well as different periods of AKI remain different. In critically ill patients and those with multiple comorbidities, identifying the underlying cause of AKI remains challenging. As an AKI biomarker, urinary NGAL, can help facilitate the differential diagnosis of chronic disease and intrinsic, pre-renal or post-renal etiologies at an early stage. As damage to the renal tubules is gradually repaired, the expression level of NGAL may decline (Romejko et al., 2023). Therefore, a drop in NGAL may indicate both a recovery of renal function and an improvement in renal tubular function. Research has demonstrated that baicalin can reduce NGAL level (Le et al., 2021). It is more sensitive than SCr, and When kidney cells are under stress or are damaged, this gene is expressed quickly. It is essential to identify AKI as soon as possible. Normal kidneys and other organs typically express the KIM-1 protein at low levels. However, its expression is notably upregulated in IRI rat kidneys and in rodent models of drug-induced AKI (Schrezenmeier et al., 2017). According to some authors, patients with AKI may experience histologic alterations prior to elevated Kim-1 levels (Zhang P. L. et al., 2008), implying that Kim1 could be one of the indicators for preferential detection of renal injury. In two studies on baicalin in the treatment of AKI, the authors detected changes in Kim1 reduction (Le et al., 2021; Shi et al., 2019). Although the above markers can be used to assess a certain degree of acute kidney injury, they all have limitations in diagnostic sensitivity and specificity, are susceptible to interference by multiple factors, and are still limited in early diagnosis and accurate assessment of the degree of injury. Hence, the pursuit of more precise and sensitive biomarkers remains a crucial objective in the investigation of AKI.

In conclusion, the anti-inflammatory, anti-oxidative stress and anti-apoptotic effects of baicalin in the treatment of AKI may be related to each other and jointly promote kidney protection. There is a close interaction between these three mechanisms, forming a complex network. For example, inflammatory responses can promote oxidative stress, and vice versa. After the release of inflammatory factors, ROS generation will be induced and the oxidative damage of cells will be aggravated. In addition, oxidative stress can also further activate inflammatory pathways, leading to apoptosis. Therefore, Baicalin can simultaneously reduce the occurrence of apoptosis by inhibiting inflammation and oxidative stress. Baicalin reduced ROS production by inhibiting inflammatory mediators, suggesting a positive feedback relationship between inflammatory response and oxidative stress (Li et al., 2022; Chen et al., 2024). Since oxidative stress can induce cell apoptosis, Baicalin reduces the risk of cell apoptosis by enhancing the activity of antioxidant enzymes, forming a virtuous cycle of antioxidant and anti-apoptosis (Li et al., 2022). The release of inflammatory mediators not only causes oxidative stress, but also directly promotes cell apoptosis. By inhibiting the expression of pro-inflammatory factors, Baicalin can effectively reduce the activation of apoptosis signal, thereby protecting the survival of kidney cells (Li et al., 2022; Zhu et al., 2016).

Damage to tubular epithelial cells, glomerulosclerosis, inflammatory infiltrates, apoptosis, and interstitial fibrosis are typical pathologic characteristics of DN. The correlation between oxidative stress and DN has been well-documented in research. Research has demonstrated that mitigating oxidative stress can alleviate the manifestations linked to streptozotocin (STZ)-induced DN (Thallas-Bonke et al., 2008). Pathological and histological observations revealed that rats in the DN group had severe inflammatory lesions, glycogen deposition, and renal fibrosis, and treatment with baicalin had a significant ameliorating effect on these pathological changes. TGF-β has gained clinical recognition as a vital factor in the pathogenesis of ESRD (Meng et al., 2016) and has attracted widespread attention. Renal tubular epithelial cells can be differentiated into fibroblasts during the process of DN through various pathways (including autocrine and paracrine), accelerating tubulointerstitial fibrosis. As a major component of the cytoskeleton, α-SMA is important in the diagnosis and differential diagnosis of fibrosis. According to certain research, α-SMA is significantly expressed in the DN rats’ renal tissues, which can be used as an indicator of fibrosis detection (Zeng et al., 2019). Baicalin treatment significantly improved both renal fibrosis and renal function in this animal model by reducing TGF-β1 and α-SMA protein expression (Hu et al., 2017). The progression of DN is facilitated by TGF-β1 through its regulation of glomerular and tubulointerstitial fibrosis, a process that relies on Smad2 and Smad3 phosphorylation and activation. There is growing evidence that in the context of kidney injury, epithelial-mesenchymal transformation (EMT) occurs, in which renal tubular epithelial cells lose their phenotypic markers (including n-cadherin and e-cadherin) and transform into fibroblasts, myofibroblasts, or mesenchymal cells, acquiring mesenchymal phenotypic markers. Includes vimentin and α-SMA (Lan, 2003). In UUO-induced renal fibrosis model, baicalin significantly decreased the expression levels of α-SMA and vimentin, and increased the expression levels of N- and e-cadherin (Zheng et al., 2017). In STZ-induced DN, baicalin can inhibit EMT by partially regulating the methylation of klotho promoter, thus alleviating renal fibrosis (Zhang X. T. et al., 2020). In addition to canonical signaling pathways (Xianyuan et al., 2019). The ECM constitutes a fundamental element of the stromal and epithelial vascular matrix, encompassing collagen fibers (types I, III, and IV), non-collagenous glycoproteins (e.g., laminin, fibronectin), proteoglycans, elastin, and aminoglycans. TGF-β1 participates in both the synthesis and degradation of the ECM, thereby exerting a significant impact on the development of renal interstitial fibrosis (Yuan et al., 2022). Baicalin inhibits ECM accumulation by targeting the TGF-β1/Smad3 pathway (Zheng et al., 2017) and Notch signaling pathway (Tan et al., 2016) in rats with renal fibrosis. It also suppresses the p38 MAPK inflammatory signaling pathway and its downstream mediator NF-κB, thereby retarding the advancement of renal fibrosis (Zheng et al., 2020). Interestingly, though, one study found that via stimulating the TGF-β/Smad signaling pathway, high dosages of baicalin could instead cause kidney damage and fibrosis (Cai et al., 2017). The reason for this may be that it leads to accumulation of the drug, where the drug acts at other, non-specific targets, triggering unintended side effects or toxic reactions. Therefore, attention needs to be paid not only to individual differentiation but also to dosage issues during treatment.

Research has demonstrated that DN patients who have prolonged hyperglycemia experience apoptosis and a deterioration in renal function. Additionally, renal tubular epithelial cells may undergo apoptosis in a hyperglycemic milieu (Ding et al., 2021). Tubular epithelial cells apoptosis is one of the main indicators of interstitial fibrosis and tubular atrophy (Johnson and DiPietro, 2013). Renal tubular epithelial cells from DN patients have been shown to exhibit apoptosis; however, fibrosis is delayed when renal tubular cell apoptosis is blocked (Huang F. et al., 2019). The processes of cell development, differentiation, death, environmental stress response, and inflammatory response are all impacted by activated p38 MAPK signaling (Coulthard et al., 2009). Research has demonstrated that renal inflammation and apoptosis are regularly regulated and promoted by p38 MAPK (Ren et al., 2020). In one study, Following treatment with STZ, there was a rise in caspase-3 and caspase-9 levels as well as hyperphosphorylation of p38 (Zheng et al., 2020). On the other hand, baicalin therapy decreased the production of apoptotic proteins in DN because these proteins strongly prevent apoptosis from starting in nephrotic tissues. This was accompanied by increased levels of insulin production with baicalin treatment, suggesting that baicalin may modulate the activation of the IGF-1/IGF-1R/p38 signalling pathway ameliorating STZ-induced renal fibrosis in DN rats (Zheng et al., 2020). Additionally, it has been discovered that JNK and p38, two members of the MAPK family, are upstream promoters of the mitochondrial apoptotic pathway. They can disrupt dimer formation and cellular localization to induce apoptosis through the mitochondrial pathway, or they can increase the Bax/Bcl-2 ratio (Chen et al., 2010). According to these research, the development of apoptosis and fibrosis in the kidneys is significantly influenced by p38 signaling.

Numerous studies have demonstrated the critical roles that the development of diabetes is mostly influenced by inflammation and oxidative stress (Wang et al., 2019). Studies show that renal inflammation has a major role in the development and progression of fibrosis (Lv et al., 2018). Baicalin decreases renal fibrosis in DN patients by upregulating miR-124 and inhibiting the downstream TLR4/NF-κB pathway in STZ-induced mouse model and HG-induced HK-2 cell model (Zhang S. et al., 2020). In STZ-induced DN and UUO-induced fibrosis models, baicalin was found to significantly reduce inflammation levels, including TNF-α↓, IL-6, IL-1β↓and iNOS (Ou et al., 2021; Wang et al., 2022; Singh et al., 2017). Furthermore, in a model of spontaneous DN, baicalin attenuates aberrant lipid metabolism in the kidneys of db/db mice and may exert nephroprotective effects through the SIRT1/AMPK/hNF4A pathway (Zhang et al., 2022). Baicalin was found to decrease MAPK signaling in the same model, which enhanced Nrf2 activity and HO-1 production, lowering oxidative stress and slowing the progression of the disease (Ma et al., 2021). Other results together suggest that baicalin may protect against renal fibrosis by reducing inflammation-induced IκB phosphorylation, JAK2 phosphorylation, and subsequent NF-κB and STAT3 activation and oxidative stress in HK-2 (Nam et al., 2020).

In diabetes and other CKD, renal fibrosis is often associated with metabolic disturbances that may involve abnormalities in glucose, lipid and protein metabolism (Qu and Jiao, 2023). Baicalin may modulate the course of renal fibrosis by affecting these metabolic pathways. Currently, controlling the metabolism of lipids and glucose can help treat DN (Wang et al., 2023). However, these clinically standard therapies only slow the progression of the disease, not stop it. Therefore, another approach to the treatment of DN may include using drugs to activate the body’s cytoprotective pathways. Under normal conditions, diabetic kidney injury gradually develops in db/db mice on its own. A prolonged high glucose environment can lead to excessive proliferation and thickening of glomerular mesangial cells (GMC) and glomerular basement membrane (GBM) as well as damage to podocytes (Barutta et al., 2022; Tung et al., 2018; Tervaert et al., 2010). Proximal tubular epithelial cells are very important in renal function, They are in charge of various substances’ secretion and reabsorption, and an environment with high glucose levels may cause these cells to dysfunction, which can lead to renal fibrosis (Zhang et al., 2023; Liu L. et al., 2022). In STZ-induced mouse model and HG-induced HK-2 cell model, investigations were conducted into the effects of baicalin on renal fibrosis and its molecular mechanisms. Baicalin therapy boosted insulin production and ameliorated renal fibrosis via activating the IGF-1/IGF-1R/p38 signaling pathway (Zheng et al., 2020). Disorders of lipid metabolism, in addition to those of glucose metabolism, play a vital part in the onset and progression of DN (Xu et al., 2021). The transcription of lipid genes is regulated by the HNF4 family; among these, hNF4α controls several metabolic pathways in the kidney. Using molecular docking and network pharmacology, baicalin was discovered to bind to HNF4A and SIRT1 with efficiency (Zhang Q. et al., 2020), which indicates that baicalin may play a significant role in glucose and lipid metabolism. Further experiments showed that baicalin reduced triglyceride levels, and more importantly, baicalin was reported to attenuate lipid accumulation and MPC-5 in db/db mice by the SIRT1/AMPK/hNF4A pathway, suggesting that baicalin has a potentially attractive and potent therapeutic role in DN (Zhang et al., 2022). A vital enzyme in lipid metabolism, CPT1α, also known as carnitine palmitoyltransferase 1α, is a part of the fatty acid oxidation process. Long-chain fatty acids need to be converted to their corresponding carnitine derivatives before crossing the outer mitochondrial membrane, and this conversion is facilitated by the enzyme CPT1α (Lin et al., 2024). In the context of Diabetic kidney disease (DKD), according to mRNA sequencing, CPT1α activity is significantly suppressed, which causes a series of cellular disruptions that are essential for the development of renal fibrosis (Lin et al., 2024). According to a recent study, renal tubular cell damage was reversed and mitochondrial respiration was enhanced by up-regulating CPT1α, while down-regulating CPT1α increased renal tubular injury and interstitial fibrosis (Yuan et al., 2021). Intriguingly, Studies suggest that increasing CPT1α activity can prevent renal fibrosis from developing (Miguel et al., 2021). A study shows that baicalin targets CPT1α and enhances its expression to ameliorate impaired lipid peroxidation, thereby attenuating renal fibrosis in DKD (Hu et al., 2024). In addition, apoptosis of proximal tubular cells was also reported to be prevented by promoting CPT1α expression (Sun et al., 2018), therefore the relationship between baicalin and CPT1α, apoptosis deserves further investigation.

Similarly, multiple mechanisms play an important role in the occurrence and development of renal fibrosis. Anti-inflammation, anti-oxidative stress, anti-apoptosis and the regulation of material metabolism are related to each other in the treatment of renal fibrosis. Due to their correlation, baicalin can affect one pathway and then other pathways, such as inhibiting inflammation, inhibiting oxidative stress, and inhibiting apoptosis, which is extremely important in the treatment of renal fibrosis.