NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) is a vital sensor of the innate immune system, capable of responding to various exogenous invading pathogens and endogenous cell injury. Once the danger signal is detected, NLRP3 recruits downstream molecules to assemble into inflammasomes, which induce inflammatory cell death and trigger an inflammatory response. PANoptosis is a specific mode of inflammatory cell death that integrates the processes of pyroptosis, apoptosis, and necrosis. It is primarily driven by a multiprotein complex termed the PANoptosome. The NLRP3 inflammasome, an essential component of the PANoptosome, is implicated in the pathogenesis of several human disorders. Targeted inhibition of NLRP3 activation specifically has a notable impact on mitigating a variety of disease conditions. This review briefly describes how the NLRP3 inflammasome forms and is activated, outlines its multifaceted roles in disorders, and emphasizes the vital role of NLRP3 in PANoptosis. Additionally, we discuss the potential of NLRP3 as a target for the clinical management of associated diseases. Improved understanding of the NLRP3 inflammasome and its involvement in PANoptosis is crucial for guiding new treatment strategies.

Guben Xiezhuo Decoction (GBXZD) is an herbal compound used to treat chronic kidney disease (CKD) under the guidance of traditional Chinese medicine (TCM). Its main components are Astragalus membranaceus (Fisch.) Bunge, Codonopsis pilosula (Franch.) Nannf., Centella asiatica (L.) Urb., Salvia miltiorrhiza Bunge, Cuscuta chinensis Lam., and Rheum palmatum L.. Clinical studies have shown that it can relieve fatigue, nausea and other symptoms and improve kidney function in patients; however, its specific mechanism of action requires further study. Renal interstitial fibrosis (RIF) is the ultimate characteristic manifestation of various CKD, that cannot be cured, and appropriate treatments to delay its progression require further exploration. GBXZD, widely used in clinical practice for RIF treatment, can effectively relieve the syndrome in patients with CKD. However, the specific mechanism of action of GBXZD in RIF is unknown and requires further study. This study aimed to explore the specific effects of GBXZD on RIF through the regulation of M1 macrophages. An in vivo RIF model was obtained through unilateral ureteral obstruction (UUO), and the Sprague-Dawley (SD) rats were randomly divided into sham operation, UUO, UUO + GBXZD-low dose (GBXZD-L) and UUO + GBXZD-high dose (GBXZD-H) groups. Pathological changes in rat kidney specimens were observed using hematoxylin and eosin (HE) and Masson staining. The expression of collagen I (COL I), fibronectin (FN), α-smooth muscle actin (α-SMA), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α) was detected using immunohistochemistry, and immunofluorescence was used to detect the expression of CD86 and inducible nitric-oxide synthase (iNOS) in kidney tissue. An in vitro experiment was performed using M1 polarization model in RAW264.7 macrophages induced by lipopolysaccharide (LPS). Cells were divided into control, LPS, LPS + GBXZD-low dose (GBXZD-L) and LPS + GBXZD-high dose (GBXZD-H) groups. The changes in expression of CD86, iNOS, IL-1β, IL-6, and TNF-α were measured using western blotting, flow cytometry, immunofluorescence and enzyme-linked immunosorbent assay (ELISA). We analyzed the action pathway of GBXZD in regulating M1 polarization of macrophages using antibody microarray and verified the results using western blotting. Histopathological results showed that the UUO group exhibited significant fibrotic injury compared to the sham group. After GBXZD treatment, the degree of kidney injury, RIF, and inflammatory factor expression were lower than those in the UUO group. Compared with LPS-treated cells, the expression of the M1 markers CD86, iNOS, and pathway proteins Raf1 and p-Elk1 was down-regulated in RAW 264.7 cells treated with LPS and GBXZD. The secretion of the inflammatory factors IL-1β, IL-6, and TNF-α in the LPS group was more than that in the control group. However, the levels of these factors were significantly reduced in the GBXZD-H group compared to those in the LPS group. This study indicates that GBXZD ameliorates RIF and inhibits the inflammatory response and macrophage M1 polarization by a potential mechanism related to the downregulation of Raf1 and p-Elk1. GBXZD therefore has therapeutic potential value for patients with CKD.

Chronic kidney disease (CKD) has become a global public health problem. Tubular epithelial cell injury plays a vital role in the progression and prognosis of CKD. Therapies to protect tubular cells is the key to delaying CKD progression. Our study found that verbena, a natural traditional Chinese herb, has a potential reno-protective role in kidney diseases. However, the detailed mechanism remains unknown. In the current study, we employed adriamycin (ADR)-induced renal tubular cell injury to mimic the conditions of tubular injury in vitro. Results showed that total aqueous exact of verbena (TAEV) ameliorated ADR-induced cell disruption, loss of cellular viability, and apoptosis via inhibition of ROS-ERK1/2-mediated activation of NLRP3 signal pathway, suggesting that TAEV serves as a promising renoprotective agent in delaying the progression of CKD, while ROS-ERK1/2-mediated NLRP3 signal pathway might be a novel target in treating kidney diseases.

Guben Xiezhuo decoction (GBXZD), a traditional Chinese medicine (TCM), shows promise in treating chronic kidney disease (CKD) by reducing renal fibrosis (RF). This study seeks to uncover the exact mechanism behind GBXZD’s therapeutic effects. This study identified 14 active components and 18 specific metabolites in the serum of GBXZD-treated rats via mass spectrometry. Potential target proteins were predicted using PubChem, TCMSP, and SwissTargetPrediction databases and refined through OMIM and Genecards databases. A total of 276 proteins were filtered from these potential target proteins to develop a protein-protein interaction (PPI) network to explore the interactions between GBXZD and RF target proteins, revealing significant correlations for proteins such as SRC, EGFR, and MAPK3. Subsequently, the active components and specific metabolites were employed for molecule docking simulation to assess their interactions with EGFR protein. The effects and mechanisms of GBXZD on RF were validated in a unilateral ureteral obstruction (UUO) rat model by assessing changes in RF-related protein expressions identified from the PPI network. GBXZD showed a reduction in the phosphorylation expression of SRC, EGFR, ERK1, JNK, and STAT3. In vitro, LPS stimulated HK 2 cells treated with the identified GBXZD bioactive components trans-3-Indoleacrylic acid and Cuminaldehyde exhibited significantly enhanced viability and reduced fibrotic marker expression and p-EGFR levels. KEGG pathway analysis suggested that GBXZD’s anti-fibrotic effects might be mediated by inhibiting the EGFR tyrosine kinase inhibitor resistance and MAPK signaling pathways.

Aralia elata (Miq.) Seem. ( A. elata ) is a medicinal and edible wild vegetable, which has potential applications in the pharmaceutical and health food industries. Araloside A (Ara A) is a natural triterpenoid saponin extracted from A. elata . Chronic kidney disease (CKD) is an important public health problem worldwide. There is still a lack of effective drugs to delay the progression of renal injury. We experimentally found that Ara A can alleviate pathological renal injury, reduce proteinuria and improve renal dysfunction in model mice. This is associated with its ability to mitigate oxidative stress and regulate ferroptosis‐related proteins. In vitro experiments, we found that Ara A can inhibit ferroptosis in podocytes and protect functional proteins. Mechanically, Ara A alleviated iron accumulation and lipid peroxidation in vivo and in vitro, and played a renal protective role by influencing the solute carrier family 7a member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) signaling pathway. Through cell and animal experiments, we have verified that Ara A, a component derived from A. elata , can delay glomerulosclerosis, with the inhibition of oxidative stress and ferroptosis as its potential mechanisms of action. These results provide evidence for the utilization of A. elata as a nutraceutical for the treatment of CKD.

Introduction: Chronic kidney disease (CKD) is a progressive condition characterized by renal fibrosis, with limited therapeutic options. Asiatic acid (AA), a triterpenoid from Centella asiatica , has shown renoprotective potential, but its mechanisms remain unclear. Methods: An adenine-induced CKD mouse model was established in C57BL/6 mice. AA was administered orally at 10 or 30 mg/kg for 8 weeks. Antibiotic depletion experiments were performed to assess gut microbiota dependence. Renal function, histopathology, and fibrosis markers were evaluated. Multi-omics analyses integrated 16S rRNA sequencing, renal untargeted metabolomics, transcriptomics, and MetOrigin-based tracing. In vitro , human proximal tubular HK-2 cells were stimulated with TGF-β1 to assess the effects of key metabolites on fibrotic injury and oxidative stress. Results: AA significantly improved renal function, reduced tubular injury and collagen deposition, and restored gut barrier integrity. Antibiotic depletion experiments demonstrated that an intact gut microbiota is required for the renoprotective effects of AA supporting a functional link along the gut-kidney axis. AA remodeled the gut microbiota, notably enriching Lachnospiraceae NK4A136 group . Renal metabolomics and transcriptomics integration identified retinol metabolism as the key renal pathway rescued by AA, with 9-cis-retinal and 4-hydroxyretinoic acid negatively correlated with injury markers. In vitro , 9-cis-retinal suppressed TGF-β1-induced fibrotic markers and oxidative stress. Discussion: AA alleviates CKD in association with remodeling of the gut microbiota and reprogramming of renal retinol metabolism, supporting its potential as a dietary supplement for countering renal fibrosis and supporting kidney health.