The pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a class B G protein-coupled receptor (GPCR) that engages both G proteins and β-arrestins to mediate diverse signaling responses, yet how PAC1R adopts distinct intracellular conformations to achieve this transducer selectivity remains poorly understood. Here, we report the cryo-electron microscopy structure of PAC1R in complex with β-arrestin 1 (βarr1), revealing a core-engaged conformation. Comparison with the Gs-bound PAC1R structure shows that βarr1 engagement is associated with remodeling of the intracellular transmembrane bundle, including TM5 reorientation and inward movement of TM6, resulting in a receptor core geometry distinct from that of the G protein-bound state. Comparison with the βarr1-bound parathyroid hormone receptor 1 (PTH1R) structure further reveals both conserved and receptor-specific features of βarr1 engagement. Although outward displacement of the TM5 cytoplasmic end is observed in both PAC1R-βarr1 and PTH1R-βarr1 complexes, its specific direction and the resulting TM5-TM6 rearrangements differ between receptors, correlating with distinct βarr1 finger loop orientations within the receptor core. Together, these findings suggest that β-arrestin core engagement by class B GPCRs is accompanied by receptor-specific intracellular remodeling that may contribute to transducer selectivity in PAC1R.
The morphology and dynamics of microtubules (MTs) are controlled by the posttranslational modification of tubulins and are critical for maintaining cardiac electrophysiological homeostasis. Recent studies have revealed that vasohibin (VASH) is a detyrosinating enzyme of tubulin, and the upregulation of VASH1 (the dominant VASH isoform in the heart) induces MT detyrosination and impaired cardiac function. It remains unknown whether VASH1 participates in the pathogenesis of ventricular arrhythmia, a lethal pathological change in cardiac hypertrophy. Here, we demonstrated that significantly increased expression of VASH1 and detyrosinated α-tubulin led to greater susceptibility of the heart to ventricular arrhythmia, as indicated by an increased number of caffeine and isoproterenol-stimulated premature ventricular complexes (PVCs) on electrocardiography in transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice versus Sham mice. Cardiac-specific VASH1 overexpression induced MT detyrosination and polymerization, increasing the number of stimulated PVCs in normal mice. Optical mapping of the hearts demonstrated that VASH1 overexpression slowed electrical conductance. A mechanistic study revealed that VASH1 upregulation increased the Ca2+ spark frequency and post-pacing Ca2+-release events, disrupted the transverse tubule network, and altered the distribution of connexin-43 at gap junctions. In cultured cardiomyocytes, VASH1 overexpression similarly increased Ca2+ spark generation, which was abolished by the coexpression of tubulin tyrosine ligase (TTL) but not by TTL-E331Q, a mutant that lacks TTL catalytic activity but maintains its depolymerization effect. Furthermore, ablation of VASH1 decreased the susceptibility of TAC mice to ventricular arrhythmia by reducing the expression of arrhythmogenic substrates. In this study, we identified VASH1 as a master regulator of arrhythmogenesis in cardiac hypertrophy, reinforcing this protein as a promising therapeutic target for preventing ventricular arrhythmia.
Targeted protein degradation (TPD) has emerged as an important therapeutic strategy in recent years. Proteolysis-targeting chimeras (PROTACs) are among the most extensively studied TPD technologies that eliminate target proteins through a “degradation rather than inhibition” mechanism. This mechanism offers opportunities to target proteins that are difficult to modulate using conventional small-molecule inhibitors and may also help mitigate drug resistance. However, the development of small-molecule PROTACs remains constrained by challenges associated with druggability, target accessibility, E3 ubiquitin ligase availability, and clinical translation. BioPROTACs have subsequently emerged as an alternative degradation platform in which genetically encoded protein modules replace conventional small-molecule ligands while preserving the underlying degradation mechanism. Their molecular design enables broader target recognition, flexible E3 ligase recruitment, and improved molecular specificity. Their emerging applications span cancer, viral infections, and neurodegenerative diseases. This review summarizes the molecular mechanisms, recent advances, and emerging applications of bioPROTAC technology, evaluates the current technical challenges, discusses potential strategies to address these limitations, and highlights future directions that may facilitate its clinical translation.
Extracellular matrix (ECM) stiffness is a critical biomechanical factor that plays a key role in tumor progression, influencing tumor behavior and driving its malignancy. Transcriptional co-activator yes-associated transcriptional regulator (YAP) is a well-established mechanosensitive regulator; however, the molecular mechanisms by which matrix stiffness-mediated YAP activation promotes tumor progression through transcriptional regulation remain incompletely defined. Here, using cross-omics analysis, in vitro, and in vivo experiments, we identified ATPase Na+/K+ transporting subunit alpha 1 (ATP1A1) as a novel target of YAP/TEA domain transcription factor 4 (TEAD4) mechano-responsive transcription factor complex, whose increased expression in stiff matrix promotes tumor cell proliferation. Mechanistically, we revealed that stiff matrix promotes YAP/TEAD4 binding to the ATP1A1 promoter, thereby upregulating its expression. Increased ATP1A1 in turn promotes intracellular calcium signaling and activates the nuclear factor-kappa B (NF-κB) pathway, thereby promoting C-X-C motif chemokine ligand 1 (CXCL1) expression and secretion, and subsequently enhances tumorigenic potential. These findings demonstrate that increased matrix stiffness activates YAP/TEAD4-dependent transcriptional program and promotes ATP1A1 expression, thereby converting mechanical cues into chemical signaling output and finally promoting malignant phenotypes in the tumor. Furthermore, these findings suggest that CXCL1 may contribute to stiffness-associated tumor progression and warrant further investigation as a potential therapeutic target.
Stevioside, a natural glycoside with diverse bioactivities, holds therapeutic potential in liver diseases, but its role in cholestatic liver repair remains largely unexplored. This study investigates the regenerative efficacy and underlying mechanisms of stevioside in bile duct ligation (BDL)-induced cholestatic liver injury. A combined pre- and post-treatment regimen of stevioside (90 mg/kg) robustly mitigated hepatic damage, evidenced by reduced necrosis, suppressed inflammation, attenuated ductular reaction, and improved hepatic function. Notably, stevioside significantly stimulated hepatocyte proliferation, as indicated by increased liver-to-body weight ratios, upregulation of cell-cycle regulators (Ccnd1, Ccna2), and transcriptomic enrichment of proliferation-related pathways. Utilizing the genetic proliferation tracing system (ProTracer), we further demonstrated that stevioside preferentially promotes the regeneration of periportal (Zone 1) and midzonal (Zone 2) hepatocytes. Conversely, it constrained the expansion of biliary epithelial cells and immune cells, thereby collectively alleviating pathological ductular reaction and inflammatory infiltration. Mechanistically, stevioside activated YAP signaling in hepatocytes and remodeled bile acid metabolism, together creating a favorable microenvironment for liver regeneration. Furthermore, stevioside exhibited a favorable safety profile with no detectable hepatotoxicity, fibrosis, or tumorigenic risk under the experimental conditions. Our findings establish that stevioside repairs cholestatic injury by directly driving region-restricted hepatocyte proliferation via YAP signaling, highlighting its potential as a mechanistically innovative candidate for the treatment of cholestatic liver diseases.
Pancreatic cancer is known as the "king of cancers", mainly due to its aggressive metastatic potential and significant heterogeneity. The liver represents the most frequent site of distant metastasis in pancreatic ductal adenocarcinoma (PDAC). Currently, effective treatment options remain critically limited for patients diagnosed with PDAC-derived hepatic metastases. In our research, we integrated single-cell transcriptomic data from multiple samples to delve into the heterogeneity of epithelial cells. We identified a subtype of malignant metastatic epithelial cells and identified CYBA, which encodes the p22phox protein, as a key molecular target promoting hepatic metastasis in PDAC. Through experimental validation, we confirmed that p22phox was highly expressed in pancreatic cancer samples with hepatic metastasis, and its knockdown inhibited the migration of pancreatic cancer cells and metastasis to the liver. Mechanistically, p22phox activated the PI3K-AKT signaling pathway and increased MLC2 phosphorylation, facilitating the polymerization of motor proteins in pancreatic cancer cells and promoting tumor metastasis. NOX inhibitors were found to suppress PI3K-AKT and p-MLC2 pathways, as well as inhibit the migration of pancreatic cancer cells and metastasis to the liver. Therefore, targeting the activity of p22phox in pancreatic cancer may emerge as an effective therapeutic strategy for treating hepatic metastasis in PDAC patients.
As the second most hematological malignancy, multiple myeloma (MM) is closely associated with dysregulated AKT/mTOR signaling. However, the underlying mechanism remains unclear. In the present study, we find the AKT/mTOR signaling pathway is activated by the ring finger protein RNF6. Acting as a ubiquitin ligase, RNF6 binds to and mediates PTEN polyubiquitination, altering its stability. Further investigations reveal that RNF6 specifically induces K27-linked ubiquitination of PTEN. RNF6 also prevents PTEN from translocalization to the plasma membrane, thereby inhibiting its phosphatase activity. Consistent with this finding, RNF6 promotes the production of PI(3,4,5)P3, and when PTEN is depleted, RNF6 fails to activate AKT/mTOR signaling. Moreover, we find USP39 binds to PTEN and abolishes K27-linked polyubiquitination mediated by RNF6. Furthermore, USP39 suppresses AKT/mTOR signaling transduction activated by RNF6. In addition, RNF6 is found to promote glycolysis in myeloma cells, but this effect is inhibited by USP39. Lastly, we discovered that oleandrin, a natural product, induces K48-linked polyubiquitination of RNF6 and subsequent degradation, thereby suppressing PTEN with K27-linked polyubiquitination and the AKT/mTOR signaling pathway. In conclusion, the study identifies RNF6 and USP39 as novel ubiquitin ligases or deubiquitinases responsible for K27-linked polyubiquitination of PTEN and as novel modulators of the AKT/mTOR pathway. Targeting the RNF6/PTEN/AKT/mTOR signaling axis might represent a novel therapeutic strategy for myeloma treatment.
Ceritinib, an anaplastic lymphoma kinase (ALK) inhibitor, is associated with cardiovascular adverse events, yet the mechanisms remain incompletely understood. Here, we show that ceritinib impairs left ventricular systolic function in mice and induces cardiomyocyte apoptosis, and identify AKT (Ser473) suppression as a key initiating event. Loss of AKT activity is paralleled by reduced phosphorylation of mTOR (Ser2448) and ULK1 (Ser757), consistent with enhanced autophagy initiation. Concurrently, loss of inhibitory GSK3β (Ser9) phosphorylation correlates with impaired lysosomal function, reflected by disrupted cathepsin D maturation and reduced lysosomal acidification. This mismatch between enhanced autophagy initiation and impaired lysosomal clearance impairs autophagic flux despite preserved autophagosome-lysosome fusion, and causes mitochondrial damage, evidenced by reduced TOMM20 and HSP60 expression and membrane potential loss. Transcriptomic and functional analyses identify AKT2 as a particularly vulnerable isoform in this network. Metformin co-treatment preserves cardiac function and attenuates apoptosis. Mechanistically, metformin increases AMPK (Thr172) phosphorylation and reduces TFEB (Ser122) phosphorylation, restores CTSD maturation, and decreases LC3-II accumulation. These protective effects occur without reversing the suppressed AKT (Ser473) or GSK3β (Ser9) phosphorylation. Together, these findings establish that AKT suppression drives ceritinib cardiotoxicity through autophagic flux impairment and mitochondrial injury, and position AMPK-driven, TFEB-associated lysosomal restoration as a mechanism-based cardioprotective strategy independent of AKT recovery.
Myocardial ischemia-reperfusion (I/R) injury remains a leading cause of cardiac dysfunction and mortality worldwide. Serine/arginine-Rich Protein Kinase 3 (SRPK3) is highly expressed in cardiac muscle, yet its specific pathological role in I/R injury has not been fully characterized. In this study, we utilized cardiac-specific knockout mouse models and cardiomyocyte hypoxia/reoxygenation assays to investigate the function of SRPK3. Our results demonstrated that SRPK3 deficiency significantly preserved cardiac function, reduced infarct size, and attenuated apoptosis and oxidative stress. Conversely, SRPK3 overexpression exacerbated these pathological phenotypes. Mechanistically, by integrating transcriptomics, phosphoproteomics, and site-directed mutagenesis, we revealed that SRPK3 directly phosphorylates the Transcription Factor KLF3 at the Ser71 residue. This phosphorylation event disrupts KLF3-mediated transcriptional activation of mTOR, thereby suppressing the mTOR/P70 S6K signaling axis. Consequently, this inhibition unleashes an excessive, maladaptive autophagic flux that transitions from a homeostatic mechanism to a lethal process, further aggravating myocardial injury. Collectively, we systematically elucidate that SRPK3 acts as a detrimental regulator in myocardial I/R injury by inducing lethal autophagy via the KLF3-mTOR axis. These findings identify the SRPK3-KLF3 interaction as a critical molecular switch and offer a promising therapeutic target for managing ischemic heart disease. This figure systematically delineates the mechanistic role of SRPK3 in myocardial ischemia/reperfusion injury. Acting as a critical regulatory factor, SRPK3 phosphorylates KLF3 at the Ser71 residue and concomitantly suppresses the mTOR signaling pathway, thereby inducing excessive pathological autophagy. This dysregulated autophagic flux, characterized by increased autophagosome formation, loses its cytoprotective function and instead exacerbates cardiomyocyte apoptosis and oxidative stress, ultimately leading to deterioration of cardiac function.
Oxyberberine (OBB) has good potential neuroprotective effects. However, the poor water solubility of OBB poses a challenge to its therapeutic effects. In this study, OBB-hydroxypropyl-β-cyclodextrin (OBB-β-CD) was prepared to increase the water solubility and improve bioavailability of OBB. The neuroprotective effects of OBB-β-CD against AD were investigated using 3×Tg transgenic AD mouse model. OBB-β-CD exhibited dual regulatory capabilities in improving both behavioral deficits and pathological features of AD. OBB-β-CD was more effective than OBB in modulating the amyloid precursor protein (APP) processing and inhibiting the hyperphosphorylation of Tau protein. OBB-β-CD was effective in reducing both the concentration of beta-amyloid 42 (Aβ42) and the deposition of Aβ plaques in 3×Tg mouse models. OBB-β-CD also suppressed neuroinflammation by promoting microglial polarization from an M1-like to an M2-like phenotype. Furthermore, OBB-β-CD restored the gut dysbiosis and inhibited the activation of the C-X-C motif chemokine receptor 3 (CXCR3) and the level of C-X-C motif chemokine ligand 10 (CXCL10) in the brain and colon tissues of 3×Tg mice. Simultaneously, the effect of OBB that suppressed microglial M1 and promoted M2 polarization to improve the neuronal micro-environment was verified in vitro using BV-2 cells. Importantly, OBB-β-CD showed similar anti-AD effects of knockdown of CXCR3 in 3×Tg mice, but no synergistic effects were observed in the shCXCR3 + OBB-β-CD group compared to the shCXCR3 group. Furthermore, the results of molecular docking and surface plasmon resonance (SPR) assay indicated that CXCR3 could bind with OBB. Additionally, the fecal microbiota transplantation (FMT) of fecal microbiota from the OBB-β-CD-treated 3×Tg mice (OBB-β-CD-FMT) significantly alleviated the cognitive deficits in the pseudo-germ-free 3×Tg mice via markedly suppressing the hyperphosphorylation of Tau protein, Aβ level and the activation of CXCR3 in the brain of 3×Tg mice. OBB-β-CD has good potential for further development into a therapeutic agent for AD treatment.
As primary WNT receptors, Frizzled (FZD) receptors behave as nonclassical GPCRs; however, their engagement with downstream transducers is largely unknown. Previous studies have suggested that β-arrestin recruitment to FZD receptors depends on its interaction with Dishevelled (DVL) and that this process regulates both canonical and non-canonical pathways. Here, we reveal that FZD6, which mainly mediates non-canonical WNT signalling, directly binds to β-arrestin 1 (βarr1) and report the cryo-EM structure of the FZD6-βarr1 complex, which revealed a unique shallow pocket in FZD6 for βarr1 engagement and identified arrestin-specific motifs that are distinct from those observed in previously reported FZD receptor-transducer complexes. Collectively, our findings establish a direct arrestin recruitment mechanism in FZD receptors that shares key features with arrestin engagement in classical GPCRs, suggesting that the engagement of core GPCR transducers may modulate WNT signalling specificity. These insights position FZD receptors as druggable targets akin to classical GPCRs, opening new avenues for targeting FZD receptors for a wide range of diseases, including cancer.
Although pain sensitization is among the most common conditions affecting the elderly, its underlying neural mechanisms remain unclear. Here, we found that mechanical hypersensitivity arises from enhanced glutamatergic excitability in primary somatosensory cortex due to bradykinin receptor B2 (BDKRB2) upregulation by dystrophic microglia during aging. Specifically, in vivo fiber photometry in aged mice revealed hyperactivity of glutamatergic neurons in primary somatosensory cortex of hindlimb (S1HLGlu), while chemogenetic inhibition of these neurons reverses pain hypersensitivity in aged mice. BDKRB2 expression on S1HLGlu neurons is significantly increased in aged mice, whereas its conditional knockdown restores pain sensitization, and its overexpression leads to nociceptive hypersensitivity in young mice. Moreover, chemogenetic or pharmacological inhibition of dystrophic microglia in aged mice reduces BDKRB2 levels, alleviating pain hypersensitivity. The present study thus demonstrates that microglia-mediated S1HLGlu hyperactivity drives development of aging-related pain via BDKRB2 signaling, suggesting several potentially effective therapeutic targets for treating geriatric pain.
Primary Sjögren’s syndrome (pSS) is a prevalent autoimmune disorder characterized by immune cell, particularly B cell, infiltration into exocrine glands, where autoantibody production disrupts glandular architecture and secretory function. Unraveling the mechanisms that drive this B cell trafficking could unveil innovative therapeutic avenues for pSS. We report that phosphodiesterase 4D (PDE4D) is markedly up-regulated in glandular epithelial cells from both pSS patients and murine models, correlating tightly with diminished saliva output and heightened B cell infiltration. Mechanistically, lipopolysaccharide (LPS) engages Toll-like receptor 2/4 signaling in human salivary gland epithelial cells to induce PDE4D expression. Then, PDE4D reduces the phosphorylation of FOXO1 and enhances its nuclear translocation and stability; in turn, FOXO1 amplifies C-X-C motif chemokine ligand 13 (CXCL13) secretion that promotes B cell chemotaxis. To interrogate the functional relevance of PDE4D, we generated pSS models in PDE4D-knockout and wild-type (WT) mice, and additionally treated WT-pSS mice with a selective PDE4D inhibitor. Genetic deletion or pharmacologic inhibition of PDE4D augmented PKA-mediated FOXO1 phosphorylation, suppressed CXCL13 expression in glandular epithelial cells, and significantly attenuated disease manifestations. Collectively, our findings position PDE4D as a promising therapeutic target for pSS.
The sigma-1 receptor (S1R), which functions as both a receptor and molecular chaperone, plays pivotal roles in various biological processes. Its widespread involvement in central neurotransmitter regulation positions S1R as a potential target for neuropsychiatric disorders, including drug addiction, schizophrenia and neurodegenerative diseases. However, the mechanisms underlying the heightened susceptibility of individuals with S1R deficiency to neurological diseases remain elusive. This study investigated the neuromodulatory role of S1R in pyramidal neurons in the barrel field of the primary somatosensory cortex (S1BF) and the medial prefrontal cortex (mPFC) in young mice across three developmental time points (postnatal days 14, 21, and 28). By employing whole-cell recordings, we revealed distinct effects of S1R on sEPSCs, sIPSCs, and the excitatory/inhibitory (E/I) balance during the critical period. Specifically, S1R-/- mice at P21 had substantially reduced sIPSC frequency, resulting in a noteworthy increase in the excitatory/inhibitory (E/I) ratio. In contrast, at P14 and P28, the sEPSCs and sIPSCs of the S1R-/- mice were not affected. Adult knockout mice exhibited drug-induced behavioral sensitization to methamphetamine (METH). Mechanistic studies revealed that the administration of METH caused an E/I imbalance of pyramidal neurons in the mPFC and a decrease in the density of dendritic spines, which was accompanied by a decrease in the protein levels of brain-derived neurotrophic factor (BDNF). SOMCL-668, an allosteric modulator of S1R, attenuated METH-induced behavioral sensitization in a dose-dependent manner through attenuating excitatory synaptic transmission and modulating the p-CREB/CREB ratio. Collectively, our results underscore the developmental dynamics of S1R-mediated regulation of synaptic plasticity, offering significant implications for treatment strategies targeting S1R deficiency and disruptions in E/I balance. Finally, our findings demonstrated that S1R is involved in METH-induced behavioral sensitization and that SOMCL-668 could be a potential therapeutic agent for drug addiction.
The coexistence of atherosclerosis and cancer is increasingly common, yet the influence of tumors on atherogenesis remains poorly understood. In this study, we investigated the impact of colorectal cancer (CRC) on atherosclerosis and elucidated the underlying mechanisms. We analyzed clinical data from patients with concurrent atherosclerosis and CRC and established three murine models of atherosclerosis comorbidity: ApoE-/- and Ldlr-/- mice bearing subcutaneous MC38 tumors, and APCmin/+ApoE-/- mice with spontaneous intestinal adenomas. We found that both patients and mice with concurrent tumors exhibited reduced plaque burden and enhanced plaque stability. Integrative multi-omics analysis comprising single-cell RNA sequencing, spatial transcriptomics, metabolomics, and bulk RNA sequencing revealed that tumors systemically deplete arginine, leading to adaptive metabolic reprogramming of intraplaque T cells toward an oxidative phosphorylation (OXPHOS)-dominant state. This metabolic shift was associated with reduced cytotoxic T-cell infiltration, suppressed pro-inflammatory effector programs, and weakened T cell-macrophage interactions, collectively establishing a low-inflammatory plaque microenvironment. Importantly, dietary arginine supplementation restored T-cell activation and reversed the CRC-mediated atheroprotective effects. These findings reveal a critical role of T-cell immunometabolic reprogramming in cancer-atherosclerosis comorbidity, demonstrate the pronounced context-dependent effects of arginine in advanced atherosclerosis, and highlight plaque-targeted immunometabolic interventions as a promising strategy to modulate plaque progression and stability.
Diabetic cardiomyopathy (DCM) is a severe complication of diabetes characterized by myocardial dysfunction and inflammatory cell death. While apoptosis repressor with caspase recruitment domain (ARC) is a known inhibitor of apoptosis, its potential role in regulating pyroptosis, a critical driver of diabetic cardiac injury-remains unexplored. In this study, we identified ARC as a potent endogenous suppressor of cardiomyocyte pyroptosis that is pathologically depleted in models of diabetes. Our findings demonstrated that overexpression of ARC, both in vitro and in diabetic mouse models, significantly alleviates high glucose-induced cardiomyocyte pyroptosis and cardiac dysfunction. We revealed that mechanistically, ARC binds to the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) via its CARD domain, thereby sequestering ASC and preventing NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome assembly. However, under hyperglycemic conditions, we found that ARC undergoes aberrant O-GlcNAcylation at the Ser-104 residue. This modification destabilizes ARC by promoting its ubiquitin-proteasomal degradation, which subsequently releases ASC to trigger NLRP3-mediated pyroptosis. Furthermore, pharmacological inhibition of O-GlcNAcylation or restoration of ARC levels effectively rescued cardiomyocytes from pyroptotic death. In summary, our study elucidated a novel pathogenic "glucose-O-GlcNAc-ARC-pyroptosis" axis in DCM, revealing that hyperglycemia-induced O-GlcNAcylation compromises the protective function of ARC. These findings suggest that targeting the O-GlcNAc-ARC interaction represents a promising therapeutic strategy for diabetic cardiomyopathy.
The pathological progression of ischemic stroke is driven by a dynamic signaling network mediated by protein-protein interactions (PPI) that involves excitotoxicity, oxidative stress, neuroinflammation, and regulated cell death (RCD), ultimately leading to neurological dysfunctions. Instead of functioning independently, these PPI-driven pathways engage in extensive cross-talk, creating cycles that exacerbate the injury over both space and time. Therapeutic strategies designed to disrupt key nodal PPIs, comprising small molecule inhibitors, peptide mimetics, and chimeras targeting proteolysis (PROTACs), have shown promise. However, clinical translation faces several major challenges, including the structural complexity of PPIs, the efficiency of blood-brain barrier (BBB) penetration, and the adaptive, multifactorial nature of the ischemic cascade. Emerging approaches are now shifting from single-target inhibition to network-level intervention, utilizing artificial intelligence (AI)-guided drug development, multi-target PPI regulators, and context-responsive delivery systems to achieve spatiotemporal precision. Through the integration of multidisciplinary technologies and mechanism-driven innovative designs, PPI-targeted strategies provide a promising approach to reprogramming the ischemic brain for repair, moving beyond traditional neuroprotection to dynamic network medicine.
Liver fibrosis, a pathological process characterized by excessive production of extracellular matrix (ECM) and sustained activation of hepatic stellate cells (HSCs), can further progress into cirrhosis and hepatocellular carcinoma. The disorder has imposed a heavy burden on global public health, resulting in millions of deaths annually. Mitophagy maintains mitochondrial function by eliminating dysfunctional mitochondria and regulating the biogenesis of new ones. It has been reported that mitophagy participates in the progression of liver diseases. However, the exact function of mitophagy in liver fibrosis remains unclear. In this review, we first outline the current knowledge regarding mitophagy regulatory mechanism. We then focus on the effect of mitophagy in the progression of liver fibrosis by regulating HSCs activation, oxidative stress, inflammatory signaling cascades, lipid metabolism reprogramming, and the modulation of the immune microenvironment. We further highlight that mitophagy mainly plays a protective role against liver fibrosis, whereas excessive mitophagy may exacerbate liver fibrosis by clearing healthy mitochondria aberrantly. Moreover, we summarize clinical data supporting mitophagy-targeted therapeutic strategies for liver fibrosis. Elucidation of these issues will offer new perspectives on the function of mitophagy during liver fibrosis, as well as potential strategies for anti-fibrotic therapy.
The human gut microbiota constitutes the largest and most metabolically active microbial ecosystem in the body, and accumulating evidence links dynamic alterations in microbial composition and function to the initiation, progression, and treatment responses of multiple gastrointestinal (GI) cancers, including esophageal, gastric, hepatocellular, pancreatic, and colorectal malignancies. This review synthesizes current evidence on dysbiosis signatures, mechanistic pathways, and translational opportunities across major GI cancer types, with a focus on microbe-derived metabolites and microbe-associated molecular patterns that shape inflammation, epithelial barrier integrity, and antitumor immunity. Across GI cancers, recurrent patterns include enrichment of pro-inflammatory/pathobiont taxa, depletion of homeostasis-maintaining and butyrate-producing commensals, and perturbations in metabolic axes centered on bile acids and short-chain fatty acids. Mechanistically, these changes can remodel the tumor microenvironment via epithelial and immune signaling, epigenetic regulation, and metabolic reprogramming. Importantly, the gut microbiota is increasingly recognized as a modifiable determinant of the efficacy and toxicity of immune checkpoint blockade, adoptive cell therapies, chemotherapy, and radiotherapy. Despite rapid advances, key challenges persist in translating microbiome research into cancer care, including validation, standardization, variability, and safety. Future success likely depends on function-oriented, targeted modulation, supported by multi-omics, strong causal evidence, and clinical trials.
