Obstructive nephropathy is one of the leading causes of kidney injury in infants and children. Increasing evidence has shown that transcription-related factors (TRFs), including transcription factors and cofactors, are associated with kidney diseases. However, a global landscape of dysregulated TRFs in pediatric patients with obstructive nephropathy is lacking.

We mined the data from our previous proteomic study for the TRF profile in pediatric patients with obstructive nephropathy and unilateral ureteral obstruction (UUO) mice. Gene ontology (GO) analysis was performed to determine pathways that were enriched in the dysregulated TRFs. We then took advantage of kidney samples from patients and UUO mice to verify the selected TRFs by immunoblots.

The proteomes identified a total of 140 human TRFs with 28 upregulated and 1 downregulated, and 160 murine TRFs with 88 upregulated and 1 downregulated (fold change >2 or <0.5). These dysregulated TRFs were enriched in the inflammatory signalings, such as janus kinase/signal transducer and activator of transcription (JAK-STAT) and tumor necrosis factor (TNF) pathways. Of note, the transforming growth factor (TGF)-β signaling pathway, which is the master regulator of organ fibrosis, was enriched in both patients and mice. Cross-species analysis showed 16 key TRFs that might mediate obstructive nephropathy in patients and UUO mice. Moreover, we verified a significant dysregulation of three previously unexplored TRFs; prohibitin (PHB), regulatory factor X 1 (RFX1), and activity-dependent neuroprotector homeobox protein (ADNP), in patients and mice.

Our study uncovered key TRFs in the obstructed kidneys and provided additional molecular insights into obstructive nephropathy.

The activation of STING1 can lead to the production and secretion of cytokines, initiating antitumor immunity. Here, we screened an ion channel ligand library and identified tetrandrine, a bis-benzylisoquinoline alkaloid, as an immunological adjuvant that enhances antitumor immunity by preventing the autophagic degradation of the STING1 protein. This tetrandrine effect is independent of its known function as a calcium or potassium channel blocker. Instead, tetrandrine inhibits lysosomal function, impairing cathepsin maturation, and autophagic degradation. Proteomic analysis of lysosomes identified TAX1BP1 as a novel autophagic receptor for the proteolysis of STING1. TAX1BP1 recognizes STING1 through the physical interaction of its coiled-coil domain with the cyclic dinucleotide binding domain of STING1. Systematic mutation of lysine (K) residues revealed that K63-ubiquitination of STING1 at the K224 site ignites TAX1BP1-dependent STING1 degradation. Combined treatment with tetrandrine and STING1 agonists promotes antitumor immunity by converting "cold" pancreatic cancers into "hot" tumors. This process is associated with enhanced cytokine release and increased infiltration of cytotoxic T-cells into the tumor microenvironment. The antitumor immunity mediated by tetrandrine and STING1 agonists is limited by neutralizing antibodies to the type I interferon receptor or CD8+ T cells. Thus, these findings establish a potential immunotherapeutic strategy against pancreatic cancer by preventing the autophagic degradation of STING1.

Contrast-induced acute kidney injury (CI-AKI) continues to pose a pressing clinical challenge during invasive cardiovascular procedures due to the limited availability of preventative strategies. We aimed to demonstrate that irisin, a myokine induced by exercise, protects against CI-AKI by inhibiting the cGAS-STING inflammatory pathway.

We explored the relationship between serum irisin levels and CI-AKI incidence in patients administered the contrast media iohexol. Notably, lower serum irisin levels were strongly associated with an increased incidence of CI-AKI following contrast media administration. To establish a causal link between serum irisin levels and CI-AKI, we utilised a mouse model that simulates exercise by overexpressing muscle-specific PGC-1α. This approach showed a significant reduction in tubular injury and mitochondrial dysfunction induced by iohexol via cGAS/STING suppression, thereby diminishing inflammation. Mechanistically, irisin was found to inhibit the activation of cGAS/STING, preventing double stranded DNA (dsDNA) leakage and reducing inflammation in tubular epithelial cells (TECs). Pharmacological inhibition of STING further corroborated these observations. Moreover, we identified integrin complex αV/β5 as the irisin receptor on TECs, which is essential for irisin-mediated suppression of cGAS-STING signalling and resolution of inflammation.

Our data position irisin as a crucial factor in muscle‒kidney crosstalk, inhibiting cGAS-STING signalling and preventing dsDNA leakage via integrin αV/β5 in TECs, thus mitigating tubular injury and inflammation. These data underscore the potential of irisin as both a predictive biomarker for CI-AKI and a promising candidate for preventative strategies against CI-AKI.

Irisin mediated muscle-kidney crosstalk mitigated tubular injury and inflammation. Irisin inhibited the cGAS-STING signalling activation via integrin αV/β5 in tubular epithelial cells. Irisin was a predictive biomarker and a promising candidate for CI-AKI.

Orthodontic tooth movement (OTM) depends on periodontal ligament cells (PDLCs), which sense biomechanical stimuli and initiate alveolar bone remodeling. Light (optimal) forces accelerate OTM, whereas heavy forces decelerate it. However, the mechanisms by which PDLCs sense biomechanical stimuli and affect osteoclastic activities under different mechanical forces (MFs) remain unclear. This study demonstrates that mechanosensitive ion channel Piezo1-mediated Ca2+ signal conversion is crucial for sensing and delivering biomechanical signals in PDLCs under heavy-force conditions. Heavy MF up-regulated Piezo1 in PDLCs, reducing mitochondrial Ca2+ influx by inhibiting ITPR3 expression in mitochondria-associated membranes. Decreased mitochondrial calcium uptake led to reduced cytoplasmic release of mitochondrial DNA and inhibited the activation of the cGAS‒STING signaling cascade, subsequently inhibiting monocyte-to-osteoclast differentiation. Inhibition of Piezo1 or up-regulation of STING expression under heavy MF conditions significantly increased osteoclast activity and accelerated OTM. These findings suggest that heavy MF-induced Piezo1 expression in PDLCs is closely related to the control of osteoclast activity during OTM and plays an essential role in alveolar bone remodeling. This mechanism may be a potential therapeutic target for accelerating OTM.

The endoplasmic reticulum (ER) is a crucial cellular organelle involved in protein synthesis, folding, modification, and transport. Exposure to internal and external stressors can induce endoplasmic reticulum stress (ERS), leading to abnormal protein folding and ER malfunction. This stress can disrupt lipid synthesis, metabolism, and transport processes. Fatty acid oxidation is the primary energy source for the renal system. When energy intake exceeds the storage capacity of adipose tissue, lipids accumulate abnormally in non-adipose tissues, including kidneys, liver, and pancreas. Lipids accumulate in the kidneys of nearly all cell types, including thylakoid membranous, pedunculated, and proximal renal tubular epithelial cells. Intracellular free fatty acids can significantly disrupt renal lipid metabolism, contributing to ischemia-reperfusion acute kidney injury, diabetic nephropathy, renal fibrosis, and lupus nephritis. Consequently, this study delineated the primary signaling pathways and mechanisms of the ERS-induced unfolded protein response, explored the mechanistic link between ERS and lipid metabolism, and elucidated its role in renal lipid metabolism. This study aimed to offer new perspectives on managing and treating renal disorders.

Manganese (Mn), the third most abundant transition metal in the earth's crust, has widespread applications in the emerging field of organometallic catalysis and traditional industries. Excessive Mn exposure causes neurological syndrome resembling Parkinson's disease (PD). The pathogenesis of PD is thought to involve microglia-mediated neuroinflammatory injury, with mitochondrial dysfunction playing a role in aberrant microglial activation. In the early stages of PD, PINK1/Parkin-mediated mitophagy contributes to the microglial inflammatory response via the cGAS/STING signaling pathway. Suppression of PINK1/Parkin-mediated mitophagy due to excessive Mn exposure exacerbates neuronal injury. Moreover, excessive Mn exposure leads to neuroinflammatory damage via the microglial cGAS-STING pathway. However, the precise role of microglial mitophagy in modulating neuroinflammation in Mn-induced parkinsonism and its underlying molecular mechanism remains unclear. Here, we observed that Mn-exposed mice exhibited neurobehavioral abnormalities and detrimental microglial activation, along with increased apoptosis of nerve cells, proinflammatory cytokines, and intracellular ROS. Furthermore, in vivo and in vitro experiments showed that excessive Mn exposure resulted in microglial mitochondrial dysfunction, manifested by increased mitochondrial ROS, decreased mitochondrial mass, and membrane potential. Additionally, with the escalating Mn dose, PINK1/Parkin-mediated mitophagy changed from activation to suppression. This was evidenced by decreased levels of LC3-II, PINK1, p-Parkin/Parkin, and increased levels of p62 protein expression level, as well as the colocalization between ATPB and LC3B due to excessive Mn exposure. Upregulation of mitophagy by urolithin A could mitigate Mn-induced mitochondrial dysfunction, as indicated by decreased mitochondrial ROS, increased mitochondrial mass, and membrane potential, along with improvements in neurobehavioral deficits and attenuated detrimental microglial activation. Using single-nucleus RNA-sequencing (snRNA-seq) analysis in the Mn-exposed mouse model, we identified the microglial cGAS-STING signaling pathway as a potential mechanism underlying Mn-induced neuroinflammation. This pathway is associated with an increase in cytosolic mtDNA levels, which activate STING signaling. These findings point to the induction of microglial mitophagy as a viable strategy to alleviate Mn-induced neuroinflammation through mtDNA-STING signaling.

The Huangqi-Danshen decoction (HDD) is composed of Huangqi (Astragali Radix) and Danshen (Salviae Miltiorrhizae Radix et Rhizoma) and has been shown to alleviate renal fibrosis. However, the potential therapeutic mechanisms and effective components of HDD remain unclear.

Both lipid metabolism and cGAS/STING signaling play vital roles in the development and progression of renal fibrosis. However, their relationship in renal fibrosis is largely unknown. The present study aimed to investigate the antifibrotic mechanisms of HDD from the perspective of lipid remodeling and cGAS/STING signaling.

In vivo, renal fibrosis was induced by feeding male C57BL/6 mice with 0.2% adenine-diet for 28 consecutive days. The treatment groups were orally administered HDD at low, medium, and high doses of 3.4 g/kg/d, 6.8 g/kg/d, and 13.6 g/kg/d simultaneously with modeling. Renal function was evaluated by the serum levels of urea nitrogen and creatinine, pathological changes of renal tissue were evaluated by Periodic acid-Schiff and Masson's trichrome staining, and renal lipid metabolites were analyzed by lipidomics. Western blotting, immunohistochemistry, and immunofluorescence were used to detect the expressions of fibrosis-related proteins, SCD1, and cGAS/STING signaling-related proteins in renal tissue. In vitro, mouse primary proximal tubular epithelial cells (PTECs) were treated with transforming growth factor-β1 (TGF-β1) or stearoyl-CoA desaturase 1 (SCD1) inhibitor A939572. Additionally, UHPLC-QE-MS analysis and TCMSP database were used to screen the effective components of HDD, and the action mechanisms of these components were verified in mouse primary PTECs.

HDD dose-dependently improved renal function, pathological injury, and fibrosis in adenine-induced chronic kidney disease (CKD) mice model. Moreover, cGAS/STING signaling was significantly activated in fibrotic kidney and was suppressed by HDD treatment. In renal lipidomics analysis, 521 and 138 differential lipids were identified in control vs. CKD and CKD vs. CKD + HDD, respectively. Of note, lipids increased in fibrotic kidneys were more saturated (fewer double bonds), whereas lipids increased by HDD were less saturated (more double bonds). Further, SCD1 expression was significantly down-regulated in fibrotic kidney and could be restored by HDD treatment. The expression of SCD1 was also down-regulated in Ju CKD patients' dataset and TGF-β1-induced fibrogenic responses in mouse primary PTECs. Mechanistically, specific inhibition of SCD1 expression could activate cGAS/STING signaling in primary PTECs. In addition, three components of HDD (isoimperatorin, baicalin, and miltirone) were screened out. Furthermore, administration of these three components, especially isoimperatorin and miltirone, counteracted the activation of cGAS/STING signaling induced by SCD1 pharmacological inhibition.

HDD could alleviate renal fibrosis, which may be related to the regulation of cGAS/STING signaling through targeting SCD1.

Maladaptive kidney repair after injury is associated with a loss of mitochondrial homeostasis, but the underlying mechanism is largely unknown. Moreover, it remains unclear whether this mitochondrial change contributes to maladaptive kidney repair or the development of chronic kidney problems after injury. Here, we report that the transcriptional coactivator peroxisome proliferation-activated receptor γ coactivator-1α (PGC1α), a master regulator of mitochondrial biogenesis, was persistently downregulated during maladaptive kidney repair after repeated low-dose cisplatin nephrotoxicity or unilateral ischemia/reperfusion injury. Administration of the PGC1α activator ZLN005 after either kidney injury not only preserved mitochondria but also attenuated kidney dysfunction, tubular damage, interstitial fibrosis, and inflammation. PGC1α downregulation in these models was associated with p53 activation. Notably, knockout of p53 from proximal tubules prevented PGC1α downregulation, attenuated chronic kidney pathologies and minimized functional decline. Inhibition of p53 with pifithrin-α, a cell permeable p53 inhibitor, had similar effects. Mechanistically, p53 bound to the PGC1α gene promoter during maladaptive kidney repair and this binding was suppressed by pifithrin-α. Together, our results indicate that p53 is induced during maladaptive kidney repair to repress PGC1α transcriptionally, resulting in mitochondrial dysfunction for the development of chronic kidney problems. Activation of PGC1α and inhibition of p53 may improve kidney repair after injury and prevent the development of chronic kidney problems.

Tubulointerstitial fibrosis is a common pathway of the progressive development of chronic kidney diseases (CKD) with different etiologies. The transcription factor interferon regulatory factor 5 (IRF5) can induce anti-type I interferons and proinflammatory cytokine genes and has been implicated as a therapeutic target for various inflammatory and autoimmune diseases. Currently, no experimental evidence has confirmed the role of IRF5 in CKD. Our results showed that IRF5 was aberrantly upregulated in fibrotic kidneys of CKD patients and was colocalized with tubular epithelial cells, peritubular endothelial cells and kidney interstitial fibroblasts. Up-regulation of IRF5 was also seen in unilateral ureteral obstruction (UUO), unilateral ischemia reperfusion and repeated low-dose cisplatin induced mice models, as well as TGF-β1-stimulated tubular epithelial cells and interstitial fibroblasts. Knockdown of Irf5 aggravated the degree of renal fibrosis in UUO mice. Consistently, overexpression of Irf5 attenuated TGF-β1-induced partial epithelial-to-mesenchymal transition and endothelial mesenchymal transition, as well as renal interstitial fibroblast activation and proliferation. Mechanistically, IRF5 can bind to the promoter region of Tgfbr1 and inhibit its transcription, thus inhibiting pro-fibrosis TGF-β1/Smad3 signal transduction. In summary, this research revealed an anti-fibrotic effect of exogenous IRF5 in tubular epithelial cells, endothelial cells and intestinal fibroblasts via transcriptionally repressing Tgfbr1. Activating IRF5 could therefore be a novel therapeutic strategy in the prevention of renal fibrosis.

Ferroptosis, a recently identified form of regulated cell death, is characterized by lipid peroxidation and iron accumulation, plays a critical role in early brain injury after subarachnoid hemorrhage. Ginsenoside Rd, an active compound isolated from ginseng, is known for its neuroprotective properties. However, its influence on SAH-induced ferroptosis remains unclear. In this study, we constructed an SAH model using intravascular perforation in vivo and treated HT22 cells with oxyhemoglobin to simulate the condition in vitro. We observed significant changes in ferroptosis markers, including GPX4 and ACSL4, following SAH. Administration of ginsenoside Rd to both rats and HT22 cells effectively inhibited neuronal ferroptosis induced by SAH, alleviating neurological deficits and cognitive dysfunction in rats. Notably, the neuroprotective properties of ginsenoside Rd were countered by the STING pathway agonist 2'3'-cGAMP. Experiments conducted in vitro and in vivo illustrated that the impacts of ginsenoside Rd were counteracted by the BQR inhibitor. Our findings suggest that ginsenoside Rd mitigates EBI after SAH by suppressing neuronal ferroptosis through the cGAS/STING pathway while upregulating DHODH levels. These outcomes emphasize the potential of ginsenoside Rd as a therapeutic candidate for subarachnoid hemorrhage.

Ectopic lipid deposition, mitochondrial injury, and inflammatory responses contribute to the development of diabetic kidney disease (DKD); however, the mechanistic link between these processes remains unclear. In this study, we demonstrate that the ceramide synthase 6 (CerS6) is primarily localized in podocytes of the glomeruli and is upregulated in two different models of diabetic mice. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses in male diabetic mice and in male mice with adriamycin-induced nephropathy. In contrast, podocyte-specific overexpression of CerS6 sufficiently induces proteinuria. Mechanistically, CerS6-derived ceramide (d18:1/16:0) can bind to the mitochondrial channel protein VDAC1 at Glu59 residue, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and ultimately promoting an immune-inflammatory response in the kidney. Importantly, CERS6 expression is increased in podocytes from kidney biopsies of patients with DKD and focal segmental glomerulosclerosis (FSGS), and the expression level of CERS6 is correlated negatively with glomerular filtration rate and positively with proteinuria. Thus, our findings suggest that targeting CerS6 may be a potential therapeutic strategy for proteinuric kidney diseases.

Liver fibrosis (LF) is a common pathological process in the progression of multiple chronic liver diseases to cirrhosis, affecting millions of people worldwide annually. The incomplete understanding of its mechanisms has led to a lack of clinically effective therapeutic options. ErTao decoction (ETD, ), a derivative combining the components of Erchen Decoction and Taohong Siwu Decoction, is rooted in the traditional Chinese medicine theory of "phlegm-dampness-blood stasis". However, the precise mechanism by which ETD exerts its therapeutic effects in LF remains unclear.

The purpose of study was to investigate the protective effect of ETD and elucidate its underlying molecular mechanism on LF.

In this study, we employed a multifaceted approach to evaluate the effects of ETD on LF. We used H&E staining, Sirius red staining, immunofluorescence, immunohistochemical analysis, and Western blotting to assess the protective effects of ETD in a CCl4-induced fibrosis mouse model. In vitro validation was conducted using macrophages and hepatic stellate cells to further elucidate the mechanisms involved. STING-deficient mice were used to assess its regulatory effects on liver injury, inflammatory and activation through immunohistochemical staining and Western blotting. Furthermore, UHPLCHRMS detection and computer-aided drug analysis were employed to identify and validate potential effective components of ETD for responsible for its therapeutic effects in treating LF.

In our in vivo and in vitro experiments, we found that ETD effectively reduced collagen fiber deposition and alleviated LF pathological changes by inhibiting macrophage inflammatory activation and suppressing NLRP3 and STING signaling. Notably, STING deficiency exhibited a protective effect against liver tissue injury and inhibited inflammatory activation of hepatic macrophages in LF model mice. Additionally, comprehensive analysis of the active ingredients in ETD strongly suggested that Naringin served as a pivotal bioactive constituent within ETD responsible for modulating STING signaling.

Our study highlighted the protective effects of ETD on LF by inhibiting STING-mediated macrophage activation and NLRP3 inflammasome signaling. Notably, Naringin might serve as a promising novel STING inhibitor to effectively counteract the progression of LF. These findings represented significant advances in LF research and paved the way for the development of novel therapeutic strategies.

Periodontitis is a prevalent chronic inflammatory disease characterized by alveolar bone resorption. Its progression is closely linked to oxidative stress where reactive oxygen species (ROS) generated by mitochondria exacerbate inflammation in positive feedback loops. Strategies for mitochondrial regulation hold potential for therapeutic advances. Metal-organic frameworks (MOFs) have shown promise as nanozymes for ROS scavenging. However, inability to directly regulate cellular processes to prevent further ROS production from damaged mitochondria during persistent inflammation makes MOFs insufficient in treating periodontitis. This study synthesizes MnO2@UiO-66(Ce) by introducing MnO2 within nanoscale mesoporous UiO-66 type MOFs. MnO2 coupled with Ce clusters in MOF channels, forms a superoxide dismutase/catalase cascade catalytic system. More importantnly, manganese endows the MOFs with bioactive effects which enhances mitophagy, facilitating the removal of damaged mitochondria, thereby restoring long-term cellular homeostasis. The results demonstrate that this synergistic antioxidant solution MnO2@UiO-66 restores mitochondrial homeostasis and osteogenic activity of periodontal ligament cells in vitro and alleviates inflammatory bone resorption in a ligature-induced periodontitis model in vivo. The SIRT1-FOXO3-BNIP3 signaling axis plays a key role in this process. This study may provide a design strategy that combines a highly efficient cascade catalytic system with long-term regulation of cellular homeostasis to combat oxidative stress in chronic inflammation.

Chronic kidney disease (CKD) involves ongoing impairment of kidney function and structural changes. Previous studies indicated that males have a substantially higher prevalence of CKD than those observed in females. Here, we compared the gender differences in CKD development by comparing age-matched male and female mice subjected to a 0.25% adenine diet (AD) for two weeks. Male mice showed a significantly greater decrease in kidney function than female mice, as evidenced by the elevated blood urea nitrogen levels (M-AD: 160 ± 5 mg/dL, F-AD: 90 ± 4 mg/dL; p < 0.001). Furthermore, male mice kidneys exhibited pronounced tubule dilation and kidney damage, as detected by histological and biochemical methods. The extent of fibrosis was quantified using multiple biological methods, revealing a greater degree of fibrosis in male kidneys. We next indicated the inflammatory responses in the kidneys. Similar to the extent of fibrosis, AD-fed male mice showed significantly increased levels of pro-inflammatory markers, including cytokine expression and infiltration of immune cell, compared to female mice. Based on in vivo observations, the anti-inflammatory and anti-fibrotic effects of 17β-estradiol (E2) were further evaluated in vitro conditions. E2 pre-treatment significantly reduced lipopolysaccharide-induced inflammatory response through inhibition of the nuclear factor-kappa B (NF-κB) pathway in NRK52E renal epithelial cells. In NRK49F renal fibroblasts, E2 pre-treatment also reduced TGFβ-induced fibrotic responses. We further demonstrated that E2 markedly decreased fibrosis and inflammation in AD-fed mouse kidneys. Our observations revealed that male mice kidneys exhibited a heightened inflammatory and fibrotic response compared to female mice kidneys. Additionally, our findings suggest that the observed sex differences may be partially attributed to the potential anti-inflammatory and anti-fibrotic effects of E2.

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.

Non-alcoholic steatohepatitis (NASH) has no effective treatment drug. Our previous study initially found that artemether (Art) treatment significantly attenuates NSAH by regulating liver lipid metabolism. This study further elucidates new mechanisms of Art in improving liver inflammation and provides evidence for drug repurposing. Herein, we utilized HFHF diet-induced animal model and macrophage models to detect the mechanisms of Art in NASH. We confirmed that Art significantly reduced hepatic steatosis, injury, and fibrosis in a high-fat high-fructose (HFHF) diet-induced animal model. Art significantly suppressed the activation of inflammatory macrophages and secretion of pro-inflammatory cytokine (IL-1β) by reducing serum double-stranded DNA (dsDNA) levels and triggering the AIM2/Caspase-1/GSDMD signaling in vivo. dsDNA-induced Caspase-1 and PI-positive cells pyroptosis, AIM2 inflammasome activation, IL-1β, and IL-18 secretion increase were inhibited by Art in vitro. Furthermore, we found Art effectively suppressed mitochondrial DNA (mtDNA), a typical form of dsDNA, released from free fatty acid (FFA)-stressed hepatocytes, which further inhibited AIM2 inflammasome mediated-pyroptosis through decreasing the cleavage of Caspase-1/GSDMD/IL-1β. Moreover, inhibition of the AIM2 gene partly reversed the inhibitory effect of Art on macrophage pyroptosis. Impaired mitochondrial structure and function were confirmed in FFA-stressed hepatocytes and the HFHF-diet-induced NASH mouse model, which was reversed by Art treatment. The present study provides evidence for Art as a potential anti-pyroptosis therapeutic agent for NASH treatment.

Previous reports have suggested that both the endoplasmic reticulum (ER) stress and cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathways contribute to the progression of chronic kidney disease; however, the relationship between these 2 pathways in kidney injury has not been fully elucidated. Andrade-Silva et al. revealed that the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway can enhance ER stress through the protein kinase R-like ER kinase (PERK)-mediated signaling cascade in kidney tubular epithelial cells and sequentially augment fibrosis during kidney injury. Further studies are needed to elucidate the precise mechanisms by which the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway activates PERK-dependent ER stress in kidney tubular epithelial cells post injury.

Breast cancer has become the leading cause of death in women. Membrane associated ring-CH-type finger 1 (MARCHF1) is associated with the development of various types of cancer, but the exact role of MARCHF1 in breast cancer remains unclear. In our study, the higher MARCHF1 expression was observed in tumor samples of patients with breast cancer and then the role of MARCHF1 in breast cancer was further evaluated. Overexpression of MARCHF1 contributed to proliferation of cancer cells and inhibition of oxidative stress. Knockdown of MARCHF1 reduced breast cancer cell proliferation, increased mitochondrial dysfunction induced by oxidative stress, eventually aggravating cell death. In vivo, MARCHF1 promoted the tumor growth and oppositely, MARCHF1 silencing suppressed the tumor development. Moreover, MARCHF1 interacted with repressor Element-1 silencing transcription factor (REST) and facilitated its ubiquitylation and degradation. Subsequently, REST negatively regulated the transcription of mitochondrial transcription factor A (TFAM). The subcutaneous tumor formation assay in nude mice also supported these conclusions. In details, knockdown of MARCHF1 upregulated the protein expression of REST and downregulated the mRNA level of TFAM. On the contrary, MARCHF1 overexpression exhibited opposite effects. Thus, MARCHF1 is conducive to the progression of breast cancer via promoting the ubiquitylation and degradation of RSET and then the transcription of TFAM. Downregulating MARCHF1 could provide a novel direction for treating breast cancer.

Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.

Endoplasmic reticulum (ER) stress is a condition in which the ER is overwhelmed and unable to manage its protein load properly. The precise activation mechanisms and role of ER stress in kidney disease remain unclear. To study this, we performed unbiased transcriptomics analysis to demonstrate ER stress in kidneys of patients with chronic kidney disease and in mouse models of acute and chronic kidney injury (cisplatin and unilateral ureteral obstruction and reanalyzed previously published data on folic acid and mitochondrial transcription factor A(TFAM) knockout mice). Inhibiting the protein kinase RNA-like ER kinase (PERK) arm of ER stress but not activating transcription factor 6 or inositol-requiring enzyme 1, protected mice from kidney fibrosis. The stimulator of interferon genes (STING) was identified as an important upstream activator of ER stress in kidney tubule cells. STING and PERK were found to physically interact, and STING agonists induced PERK activation in kidney tubule cells. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. We also generated mice with a tubule specific STING deletion that were resistant to ER stress and kidney fibrosis. Human kidney spatial transcriptomics highlighted a spatial correlation between STING, ER stress and fibrotic gene expression. Thus, our results indicate that STING is an important upstream regulator of PERK and ER stress in tubule cells during kidney fibrosis development.

Chaihuang Yishen Granules (CHYS) has been clinically proven to be effective for the treatment of chronic kidney disease (CKD), yet its underlying molecular mechanisms remain largely unexplored.

To explore the innovative mechanisms by which CHYS alleviates CKD, focusing on its role in modulating PRDX5/TFAM-mediated mitochondrial homeostasis in renal cells.

In this study, CKD mouse model was established by unilateral ureteral obstruction (UUO) and adenine (Ade) diet. Treatment interventions were administered by gavage with CHYS at doses of 3.8g/kg (low dose) and 7.6g/kg (high dose). The ameliorative effects of CHYS on CKD were evaluated by changes in renal function, kidney tissue structure, renal fibrosis, and mitochondrial dysfunction markers. Tert‑butyl hydroperoxide (t-BHP)-induced oxidative stress in TCMK1 cells was used to simulate CKD renal fibrosis induced by mitochondrial dysfunction in vitro.

CHYS significantly improves renal function and mitigates fibrosis while restoring mitochondrial homeostasis. Notably, PRDX5 expression, which is markedly reduced in CKD patients and mouse models, is substantially upregulated following CHYS treatment. Meanwhile, we demonstrate that ultrasound microbubble-mediated in situ overexpression of PRDX5 confers considerable renal protection in the UUO model. In vitro data show that CHYS effectively prevents t-BHP-induced mtDNA leakage in renal tubular cells, preserving mitochondrial function and stability, an effect compromised by PRDX5 knockdown. Moreover, our protein binding assays uncover a previously unreported interaction between PRDX5 and TFAM, with TFAM knockdown reversing the mitochondrial functional and fibrotic improvements achieved through PRDX5 overexpression and CHYS intervention.

These findings introduce a pioneering perspective on CHYS's mechanism of action. CHYS enhance TFAM activation through PRDX5 upregulation, counteract ROS-induced mitochondrial damage, and restoring mitochondrial homeostasis, and alleviates the progression of renal fibrosis in CKD, highlighting the innovative therapeutic potential of CHYS in mitochondrial-related renal pathologies.

Acute kidney injury (AKI) is a critical clinical syndrome associated with both innate and adaptive immune responses and thus increases mortality. Nevertheless, specific therapeutics for AKI are scarce so far. Recent studies have revealed that knockout of STING alleviate AKI, suggesting that STING could be an attractive target for AKI therapy. SN-011, a promising STING inhibitor, has not been reported in studies of its anti-AKI activity. In this study, we sought to examine the effects of SN-011 on AKI and explore its underlying mechanism. Our findings indicate that SN-011 could modulate the NF-κB and MAPK pathways, suppress the expression of inflammatory factors, and decrease ROS release in the cisplatin-induced cell model. In addition, SN-011 blocked the nuclear translocation of NF-κB p65, further mitigating the inflammatory response. In vivo, SN-011 enhanced survival rates and alleviated renal dysfunction. According to gene set enrichment analysis of sequencing data from mouse kidneys, we further confirm that SN-011 modulates the NF-κB and MAPK pathways. Our study suggests that SN-011 could be an attractive anti-inflammatory agent for further anti-AKI research.

Renal fibrosis is a common pathway involved in the progression of various chronic kidney diseases to end-stage renal disease. Recent studies show that mitochondrial injury of renal tubular epithelial cells (RTECs) is a crucial pathological foundation for renal fibrosis. However, the underlying regulatory mechanisms remain unclear. Pyruvate carboxylase (PC) is a catalytic enzyme located within the mitochondria that is intricately linked with mitochondrial damage and metabolism. In the present study, the downregulation of PC in various fibrotic animal and human kidney samples is demonstrated. Renal proximal tubule-specific Pcx gene knockout mice (PcxcKO) has significant interstitial fibrosis compared to control mice, with heightened expression of extracellular matrix molecules. This is further demonstrated in a stable PC knock-out RTEC line. Mechanistically, PC deficiency reduces its interaction with sulfide:quinone oxidoreductase (SQOR), increasing the ubiquitination and degradation of SQOR. This leads to mitochondrial morphological and functional disruption, increased mtDNA release, activation of the cGAS-STING pathway, and elevated glycolysis levels, and ultimately, promotes renal fibrosis. This study investigates the molecular mechanisms through which PC deficiency induces mitochondrial injury and metabolic reprogramming in RTECs. This study provides a novel theoretical foundation and potential therapeutic targets for the pathogenesis and treatment of renal fibrosis.

Cytotoxic DNAs, methylation, histones and histones binding proteins are speculated to induce DNA sensors. Under stressed condition, the antigenic patterns, PAMPs and DAMPs, trigger the hyperactive innate response through DNA, DNA-RNA hybrids, oligonucleotides, histones and mtDNA to initiate cGAMP-STING-IFN I cascade. HSV -1&2, HIV, Varicella- Zoster virus, Polyomavirus, Cytomegalovirus, and KSHV negatively regulate the STING-MAVS-TBK-1/1KKE pathway. Implications in STING-PKR-ER regulation often run into causing senescence and organ fibrosis. Post-translational modifications such as, phosphorylation, ubiquitination, SUMOylation, hydrolysis etc. downstream the processing of cGAS-STING that determine the fate of disease prognosis. Self-DNA under normal circumstances is removed through DNase III action; however, its deficiency is the great cause of RA diseases. Regular STING activation in chronic diseases could lead to exacerbate the neurodegenerative disorders due to constant mtDNA leakage. 2' 3' cGAMP or CDN or its associates are being explored as STING agonist therapeutics to treat solid/metastatic tumors to help infiltrate the immune cells, cytokines and chemokines to regulate the protective response. Liposomes, polymer nanoparticles, and cell-derived nanoparticles are also meant to increase the drug efficiency and stability for desired immune response to enhance the IFN I production. This review highlights the implications of cGAMP-STING- IFN I cascade and related pathways involved in the disease prognosis, therapeutics and considering the gaps on different aspects to utilize its greater potential in disease control.

Although emerging studies highlight the pivotal role of podocyte senescence in the pathogenesis of diabetic kidney disease (DKD) and aging-related kidney diseases, therapeutic strategies for preventing podocyte senescence are still lacking. Here, we identified a previously unrecognized role of GPR124, a novel adhesion G protein-coupled receptor, in maintaining podocyte structure and function by regulation of cellular senescence in DKD. Podocyte GPR124 was significantly reduced in db/db diabetic (a type 2 diabetic mouse model) and streptozocin-induced diabetic mice (a type 1 diabetic model), which was further confirmed in kidney biopsies from patients with DKD. The level of GPR124 in glomeruli was positively correlated with the estimated glomerular filtration rate and negatively correlated with serum creatinine levels. Podocyte-specific deficiency of GPR124 significantly aggravated podocyte injury and proteinuria in the two models of diabetic mice. Moreover, GPR124 regulated podocyte senescence in both diabetic and aged mice. Mechanistically, GPR124 directly bound with vinculin and negatively regulated focal adhesion kinase (FAK) signaling, thereby mediating podocyte senescence and function. Importantly, overexpression of GPR124 or pharmacological inhibition of FAK protected against podocyte senescence and injury under diabetic conditions. Our studies suggest that targeting GPR124 may be an innovative therapeutic strategy for patients with DKD and aging-related kidney diseases.

Mitochondrial dysfunction and damage can result in the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activates the cGAS-STING pathway, promoting the onset of inflammatory diseases. Various factors, such as oxidative stress, viral infection, and drug toxicity, have been identified as inducers of mitochondrial damage. This study aims to investigate the role of mtDNA as a critical inflammatory mediator in the pathogenesis of ketamine (KET)-induced cystitis (KC) through the cGAS-STING pathway.

To investigate the role of the cGAS-STING pathway in KET-induced cystitis, we assessed the expression of cGAS and STING in rats with KET cystitis. Additionally, we evaluated STING expression in conditionally deficient Simian Virus-transformed Human Uroepithelial Cell Line 1 (SV-HUC-1) cells in vitro. Morphological changes in mitochondria were examined using transmission electron microscopy. We measured intracellular reactive oxygen species (ROS) production through flow cytometry and immunofluorescence techniques. Furthermore, alterations in associated inflammatory factors and cytokines were quantified using real-time quantitative PCR with fluorescence detection.

We observed up-regulation of cGAS and STING expressions in the bladder tissue of rats in the KET group, stimulation with KET also led to increased cGAS and STING levels in SV-HUC-1 cells. Notably, the knockdown of STING inhibited the nuclear translocation of NF-κB p65 and IRF3, resulting in a decrease in the expression of inflammatory cytokines, including IL-6, IL-8, and CXCL10. Additionally, KET induced damage to the mitochondria of SV-HUC-1 cells, facilitating the release of mtDNA into the cytoplasm. This significant depletion of mtDNA inhibited the activation of cGAS-STING pathway, subsequently affecting the expression of NF-κB p65 and IRF3. Importantly, the reintroduction of mtDNA after STING knockdown partially restored the inflammatory response.

Our findings confirmed the activation of the cGAS-STING pathway in KC rats and revealed mitochondrial damage in vitro. These results highlight the involvement of the cGAS-STING pathway in the pathogenesis of KC, suggesting its potential as a therapeutic target for intervention.

Acute lung injury (ALI) is a severe condition characterized by inflammation, tissue damage, and persistent activation of the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) pathway, which exacerbates the production of pro-inflammatory mediators and promotes the progression of ALI. Specific inhibition of this pathway has been shown to alleviate ALI symptoms. Kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside (KAE), an active compound found in the flowers of Angelica acutiloba Kitagawa, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the molecular mechanisms through which KAE regulates the cGAS-STING pathway in the context of ALI.

ALI was induced using LPS. Lung damage and anti-inflammatory/antioxidant effects were assessed by H&E staining, lung edema index, and SOD, MDA, and ELISA assays. NO release and mitochondrial membrane potential (MMP) were measured by JC-1 and Griess methods. The impact of KAE on the cGAS-STING pathway and PANoptosis was analyzed using flow cytometry, Western blot, and immunofluorescence.

KAE significantly alleviated lipopolysaccharide-induced pulmonary injury by reducing inflammatory cell infiltration, alleviating pulmonary edema, enhancing antioxidant capacity, and decreasing levels of inflammatory cytokines in mouse lung tissues. In both in vitro and in vivo analyses, KAE downregulated the expression of key components of the cGAS-STING pathway, including cGAS, STING, p-TBK1, and nuclear factor-κB. KAE also reduced the assembly and activation of the PANoptosome, thereby attenuating apoptosis, necroptosis, and pyroptosis. Additionally, KAE inhibited cGAS activation by restoring the MMP, which reduced the release of cytosolic DNA.

KAE improve ALI by inhibiting the release of cytosolic DNA and suppressing cGAS-STING pathway activation, thereby protecting cells from PANoptosis. Our findings provide valuable insights for the development and application of novel therapeutic strategies for ALI.

6:2 Chlorinated polyfluoroalkyl ether sulfonate (trade name F-53B) is a substitute for perfluorooctane sulfonate (PFOS) used in the plating industry, and has been found in a range of environmental matrices and livings. There are numerous ways by which it is biotoxic to mammals. The kidneys are critical for maintaining homeostasis. However, little research has been conducted on how F-53B affects the kidneys. In this work, we investigated the renal toxicity of long-term oral F-53B treatment in C57BL/6J mice. Mice were allowed to drink F-53B freely at concentrations of 0, 0.057, 0.57, and 5.7 mg/L for 8 weeks. Renal oxidative stress, inflammation, and fibrosis were detected in mice exposed to F-53B, and the expression of related biochemical markers was significantly altered. Further investigations revealed that the TGF-β1/Smad3 and NF-κB signaling pathways may be associated with F-53B-induced renal fibrotic damage and inflammation. Overall, this study suggested that F-53B causes renal injury possibly via oxidative stress, activating the TGF-β1/Smad3 and NF-κB signaling pathways. This provides a foundation for further research into the harmful mechanism of F-53B in mammals.

Chronic kidney disease (CKD) is a multifactorial health issue characterised by kidney impairment that has significant morbidity and mortality in the global population. Current treatments for CKD fail to prevent progression to end-stage kidney disease, where management is limited to renal replacement therapy or kidney transplantation. Mitochondrial dysfunction has been implicated in the pathogenesis of CKD and can be broadly categorised into abnormalities related to excessive oxidative stress, reduced mitochondrial biogenesis, excess mitochondrial fission and dysregulated mitophagy. Mitochondria-targeting therapeutic strategies target many of the outlined mechanisms of mitochondrial dysfunction, and an overview of recent evidence for mitochondria-targeting therapeutic strategies is explored in this review, including naturally derived compounds and novel approaches such as fusion proteins. Mitochondria-targeting therapeutic strategies using these approaches show the potential to stabilise or improve renal function, and clinical studies are needed to further confirm their safety and efficacy in human contexts.

As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.

Acute kidney injury induced by stings from multiple wasps is a medical emergency and is a driving factor of acute renal dysfunction. Numerous studies have shown that mitochondrial reactive oxygen species (mtROS) play a key role in ischemia-reperfusion injury-, cisplatin-, and sepsis-induced acute kidney injury. However, the role of mtROS and its underlying mechanisms in wasp-venom-induced acute kidney injury remain inconclusive. In this study, we investigated the role and mechanisms of mtROS in mitochondrial damage and inflammation in a mouse model of acute kidney injury induced using wasp venom. Changes in mitochondrial function, transcription factor A (TFAM) expression, and DNA maintenance levels, renal function, stimulator of interferon gene (STING) expression, and inflammatory mediator levels in model mice with or without the mtROS scavenger Mito-Tempo were analyzed in vivo. Downregulation of mtROS levels reversed renal damage and mitochondrial dysfunction, and reduced STING expression and inflammation in the kidneys of model mice. The suppression of mtROS levels also improved the decrease in TFAM levels and mitochondrial DNA copy numbers in the kidneys of the model mice. In summary, the existing evidence in this study shows that mtROS contribute significantly to mitochondrial damage and inflammation in acute kidney injury induced by wasp venom.

Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. It then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.

Chronic kidney disease (CKD), defined as persistent (>3 months) kidney functional loss, has a growing prevalence (>10% worldwide population) and limited treatment options. Fibrosis driven by the aberrant accumulation of extracellular matrix is the final common pathway of nearly all types of chronic repetitive injury in the kidney and is considered a hallmark of CKD. Myofibroblasts are key extracellular matrix-producing cells that are activated by crosstalk between damaged tubules and immune cells. Emerging evidence indicates that metabolic alterations are crucial contributors to the pathogenesis of kidney fibrosis by affecting cellular bioenergetics and metabolite signalling. Immune cell functions are intricately connected to their metabolic characteristics, and kidney cells seem to undergo cell-type-specific metabolic shifts in response to damage, all of which can determine injury and repair responses in CKD. A detailed understanding of the heterogeneity in metabolic reprogramming of different kidney cellular subsets is essential to elucidating communication processes between cell types and to enabling the development of metabolism-based innovative therapeutic strategies against CKD.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, primarily characterized by chronic symmetric synovial inflammation and erosive bone destruction.Mitochondria, the primary site of cellular energy production, play a crucial role in energy metabolism and possess homeostatic regulation capabilities. Mitochondrial function influences the differentiation, activation, and survival of both immune and non-immune cells involved in RA pathogenesis. If the organism experiences hypoxia, genetic predisposition, and oxidative stress, it leads to mitochondrial dysfunction, which further affects immune cell energy metabolism, synovial cell proliferation, apoptosis, and inflammatory signaling, causing the onset and progression of RA; and, mitochondrial regulation is becoming increasingly important in the treatment of RA.In this review, we examine the structure and function of mitochondria, analyze the potential causes of mitochondrial dysfunction in RA, and focus on the mechanisms by which mitochondrial dysfunction triggers chronic inflammation and immune disorders in RA. We also explore the effects of mitochondrial dysfunction on RA immune cells and osteoblasts, emphasizing its key role in the immune response and inflammatory processes in RA. Furthermore, we discuss potential biological processes that regulate mitochondrial homeostasis, which are of great importance for the prevention and treatment of RA.

Tank-binding kinase 1 (TBK1) is a critical signal transducer in the nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, essential for innate immunity. However, its negative regulation mechanisms remain unclear. This study demonstrates that TBK1 succinylation, regulated by desuccinylase SIRT5, inhibits lipopolysaccharide (LPS)/Toll-like receptor 4 (TLR4)-mediated NF-κB and IRF signaling activation. We identified three key succinylation sites on TBK1: K38, K154, and K692. In endotoxemia and sepsis models, reduced SIRT5 levels in macrophages increased TBK1 succinylation, inhibiting its binding to IRF3 and TRAF2 and suppressing the inflammatory response. In vivo, adoptive transfer of macrophages expressing the succinylation-resistant TBK1-2KR (K154/692R) mutant reversed the inflammatory cytokine suppression caused by SIRT5 deficiency, exacerbating sepsis-induced lung injury. These findings reveal a novel mechanism by which SIRT5 modulates TBK1 activity and macrophage-mediated inflammation during sepsis.