Despite the transformative advances that have been made in cancer immunotherapy, primary and acquired resistance remain prevalent, limiting durable clinical benefits. Mechanistic studies on immunotherapeutic resistance have largely focused on genetic, transcriptional, signaling, and metabolic programs within tumor and immune cells, with organelle physical routes and metabolic exchange across the tumor–host interface remaining relatively underexplored. Tunneling nanotubes (TNTs), membranous conduits that mediate long-range intercellular exchange, are increasingly implicated in tumor microenvironment remodeling. Thus, TNT-mediated mitochondrial transfer may represent an underexplored intercellular communication axis that can potentially influence tumor adaptation and immunotherapeutic responses. By enabling tumor cells to acquire functional mitochondria from neighboring stromal or immune cells, TNT-associated transfer may reinforce oxidative metabolism, redox homeostasis, and survival under immune and therapeutic pressure. Conversely, although the functional consequences of mitochondrial exchange are strongly dependent on the donor–recipient context, the transfer of tumor-derived mitochondria may result in the reprogramming of recipient immune or stromal cells and favor immunosuppressive states. However, direct evidence establishing TNT-mediated mitochondrial transfer as a causal determinant of immunotherapeutic resistance remains limited and varies significantly across therapeutic modalities. This review discusses the molecular mechanisms governing TNT formation and mitochondrial trafficking, examines the metabolic and immunological consequences of bidirectional tumor–host mitochondrial exchange, critically evaluates evidence linking these processes to distinct immunotherapeutic modalities, and discusses strategies and experimental priorities for their therapeutic translation.
Background Tau pathology is strongly associated with neurodegeneration and clinical progression in Alzheimer’s disease (AD), positioning it as an important therapeutic target. However, tau-targeted therapies have thus far demonstrated limited and inconsistent translation into meaningful clinical benefit. Objective To examine clinical trials of tau-targeted therapies and explore potential mechanisms underlying their translational disconnect between biological target engagement and clinical outcomes. Methods A structured search of PubMed, MEDLINE, Embase, Cochrane CENTRAL, and related databases was conducted to identify interventional clinical trials targeting tau pathology. Eligible studies included randomized and early-phase trials evaluating monoclonal antibodies, vaccines, antisense oligonucleotides, and small-molecule aggregation inhibitors. Findings were synthesized using a structured narrative approach due to heterogeneity in study design, disease populations, therapeutic mechanisms and clinical end points. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Results Eleven clinical trials were included, comprising seven monoclonal antibody studies, two vaccine trials, one antisense oligonucleotide study, and one small-molecule aggregation inhibitor study. Across monoclonal antibody and vaccine programs, biomarker modulation and target engagement were observed in some studies, yet these findings did not consistently translate into meaningful reductions in cognitive or functional decline. The antisense oligonucleotide BIIB080 demonstrated substantial reductions in cerebrospinal fluid tau biomarkers, supporting biological activity and target engagement; however, clinical efficacy remains to be established. Similarly, the small-molecule aggregation inhibitor LMTM did not demonstrate consistent clinical benefit in phase 3 trials. Most studies exhibited low risk of bias or some concerns, suggesting that methodological limitations alone may not fully explain the observed translational challenges. Conclusion Tau-targeted therapies highlight a translational gap between biological activity and clinically meaningful benefit across multiple therapeutic mechanisms. Emerging evidence suggests that disease-stage timing, biomarker interpretation, tau heterogeneity, and aging-related factors may contribute to this disconnect. Future strategies will likely require earlier, and more biologically stratified intervention approaches, improved biomarker validation, and combination paradigms addressing the multifactorial complexity of neurodegenerative disease.
Cancer neuroscience has expanded the conceptual landscape of tumor biology by revealing that nerves are not passive bystanders within malignant tissues, but active regulators of tumor progression, immune surveillance, and therapeutic response. Among neural components of the tumor microenvironment, nociceptive sensory neurons have emerged as critical interfaces between tissue injury, inflammation, cancer-associated pain, and immune regulation. This review proposes that nociceptive neuron-driven immune escape represents a tissue-level pathological process positioned at the intersection of cancer neuroscience, tumor immunology, and immunometabolism. We discuss how tumor-associated inflammatory mediators, extracellular acidosis, mechanical stress, metabolic perturbations, and axon-guidance programs activate nociceptors and induce the release of calcitonin gene-related peptide (CGRP) and related neuropeptides. Through receptor activity-modifying protein 1-containing receptor complexes, CGRP can suppress CD8⁺ T-cell receptor signaling, promote exhaustion-associated transcriptional and metabolic programs, impair dendritic cell function, and reinforce suppressive myeloid and regulatory immune compartments. We further examine how tumor cells may co-opt the ATF4-SLIT2-CGRP axis to establish cross-organ neuroimmune circuits extending to tumor-draining lymph nodes, thereby weakening antigen presentation, T-cell priming, and responsiveness to immune checkpoint blockade. Finally, we consider lactate accumulation and extracellular acidification as parallel immunometabolic pressures that may consolidate nociceptor-associated immune dysfunction by constraining T-cell bioenergetic fitness, promoting suppressive immune states, and potentially modulating sensory-neuron activity. Rather than defining a fixed linear pathway, we conceptualize the nociceptor-CGRP-lactate axis as an integrative neuroimmune-metabolic framework in which partially independent neural and metabolic processes converge on shared mechanisms of immune escape. This framework provides a translational rationale for evaluating combined neural, metabolic, and immune checkpoint-directed interventions in cancers characterized by neural involvement, metabolic suppression, and immunotherapy resistance.
Intervertebral disc degeneration (IDD) is a leading cause of chronic low back pain, and macrophages play a pivotal regulatory role through metabolic reprogramming that governs M1/M2 polarization. This study aimed to elucidate how the Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) axis and carnitine palmitoyltransferase 1A (CPT1A)-mediated metabolic reprogramming regulate macrophage polarization in IDD using single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (bulk RNA-seq), and isotope tracing. A puncture-induced IDD rat model was established. Exploratory scRNA-seq and bulk RNA-seq revealed an increased M1 macrophage trend and identified SIRT1, PGC-1α, and CPT1A as candidate regulators of glycolysis and fatty acid oxidation (FAO). Immunofluorescence, Western blot, and flow cytometry confirmed M1/M2 polarization changes. Lentiviral-mediated overexpression, PGC-1α/CPT1A knockdown rescue, and [¹³C]-glucose and [¹³C]-palmitate isotope tracing demonstrated that activation of the SIRT1/PGC-1α axis and CPT1A enhanced oxidative phosphorylation (OXPHOS) and FAO, reduced glycolytic activity, promoted M2 polarization, suppressed inflammatory cytokines, and mitigated extracellular matrix (ECM) degradation. In vivo administration of the SIRT1 agonist SRT1720 or CPT1A agonist C75 alleviated IDD progression. This study indicates that the SIRT1/PGC-1α/CPT1A axis regulates macrophage polarization through metabolic reprogramming and provides potential therapeutic targets for IDD.
Tauopathies encompass a heterogeneous group of neurodegenerative disorders characterized by the transition of tau from a microtubule-stabilizing protein into pathogenic, seed-competent species. Increasing evidence has redefined tau from a descriptive pathological hallmark to a pharmacologically actionable target across multiple disease stages. Therapeutic opportunities are now emerging across several interconnected modules, including microtubule-associated protein tau (MAPT) gene dysregulation, 3-repeat:4-repeat (3R:4R) tau imbalance and pathogenic post-translational modification (PTM). Additional modules involve aggregation and seeding, liquid-liquid phase separation (LLPS), prion-like propagation, co-pathological protein interactions, and downstream injury. At the nucleic acid level, antisense oligonucleotides and splice-correcting strategies reduce total tau expression or restore pathogenic isoform balance. At the protein level, active and passive immunotherapies, proteolysis-targeting chimera (PROTAC)-based degradation, and autophagy-enhancing approaches aim to lower tau burden or eliminate pathological species. PTM-directed strategies target the transition from microtubule-bound tau to toxic soluble intermediates. However, clinical translation remains constrained by limited specificity and incomplete functional benefit. Aggregation and seeding have emerged as pharmacologically tractable processes. Key targets include the amyloidogenic motifs paired helical filament 6 (PHF6; 306-311, VQIVYK) and PHF6* (275-280, VQIINK). In parallel, LLPS and tau propagation represent additional therapeutic cascades. These involve condensate maturation, seed release, cellular uptake, glial processing, glymphatic clearance. Beyond tau-centered approaches, increasing attention has also turned to amyloid-β (Aβ) and α-synuclein co-pathology. Adjunct strategies are being developed to target neuroinflammation, synaptic dysfunction, microtubule destabilization and mitochondrial stress. Collectively, current evidence supports a paradigm shift from broad pan-tau intervention toward stage-specific, species-specific, and combination-based therapeutic strategies.
Heart failure with preserved ejection fraction (HFpEF) is a major heart failure phenotype in type 2 diabetes mellitus, yet therapies directed at its underlying cardiomyocyte mechanisms remain limited. This review focuses on how diabetic metabolic, inflammatory, and structural stress remodel cardiomyocyte Ca2 + handling. Impaired sarcoplasmic reticulum Ca2+ reuptake, enhanced diastolic Ca2+ leak, reduced sarcolemmal Ca2+ extrusion, and disrupted mitochondrial Ca2+-energy coupling collectively delay Ca2+ clearance and sustain elevated end-diastolic cytosolic Ca2+, thereby contributing to impaired diastolic relaxation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors may improve Na+-Ca2+ coupling by reducing sodium-hydrogen exchanger 1 (NHE1)- and late Na+ current-mediated Na+ overload, whereas metabolic interventions such as ketone supplementation and glucagon-like peptide-1 receptor agonists may support mitochondrial energetics and Ca2+ clearance. More direct approaches, including modulation of Ca2+-handling proteins, ryanodine receptor 2 (RyR2) stabilization, sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) restoration, and repair of T-tubule-associated microdomains, remain largely preclinical or early translational. Advancing this field will require human myocardial validation, biomarkers linked to specific Ca2+ defects, and stratification of patients according to the dominant mechanism of Ca2+ dysregulation.
Upper tract urothelial carcinoma (UTUC) is characterized by a high incidence of muscle invasion and distinct molecular heterogeneity, with tumor microenvironment (TME) heterogeneity playing a pivotal role in its malignant progression. However, the spatial distribution patterns of functional cell populations in UTUC and their regulatory mechanisms driving high-grade (HG) and muscle-invasive (MI) progression remain largely unelucidated. Herein, we integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptome sequencing (ST-seq) to systematically characterize the cellular landscape, spatial molecular network, and intercellular communication profile of UTUC tissues. Six tumor cell subpopulations were identified in UTUC, among which SLC14A1⁺ tumor cells were correlated with favorable clinical prognosis, whereas S100A8/9⁺ tumor cells were associated with poor clinical outcomes. Mechanistically, SLC14A1⁺ tumor cells decelerated UTUC progression via modulating cell apoptosis mediated by the FASLG-TNFRSF10B ligand-receptor pair. In contrast, S100A8/9⁺ tumor cells promoted the malignant progression of UTUC by regulating extracellular matrix remodeling and epithelial-mesenchymal transition (EMT) via the CCL19-CCR7, CCN2-EGFR, ADAM28-ITGA4 and CD14-ITGB2 ligand-receptor pairs. Collectively, our study uncovers the cellular and spatial heterogeneity of the UTUC TME, identifies SLC14A1⁺ tumor cells as a tumor-suppressive subpopulation and S100A8/9⁺ tumor cells as a key driver of UTUC malignant progression, and further delineates the core spatial signaling pathways underlying HG and MI progression of UTUC. These findings provide novel prognostic biomarkers and potential therapeutic targets for UTUC, and advance our mechanistic understanding of spatial TME regulation in urothelial carcinoma.
Solubleamyloid-β(Aβ) assemblies, glutamate-associated injury, mitochondrial dysfunction, and synaptic failure are closely connected processes in Alzheimer's disease. Here, we investigated the neuroprotective activity of spectinabilin, a natural product isolated from the marine-derived bacterium Streptomyces spectabilis, using biochemical assays, neuronal cell models, and Caenorhabditis elegans (C. elegans) models of Aβ proteotoxicity. Spectinabilin directly associated with both monomeric and oligomer-enriched FITC-Aβ42 under microscale thermophoresis conditions, with apparent dissociation constants of 13.9 and 2.72 µM, respectively, and reduced the accumulation of ThT-positive β-sheet-rich assemblies and elongated fibrils in vitro. In differentiated HT22 cells and primary cortical neurons, spectinabilin attenuated glutamate- and oligomer-enriched Aβ42-associated reductions in cell viability and preserved mitochondrial membrane potential during Aβ42 exposure. In Aβ-expressing C. elegans, spectinabilin reduced ThS-reactive deposits and oxidative-stress-associated fluorescence, delayed paralysis, extended lifespan, and improved chemotaxis. Integrated transcriptomic analysis showed that spectinabilin partially opposed Aβ-model-associated alterations, particularly in synaptic signaling, G protein-coupled receptor-associated signaling, and membrane-potential-related pathways. Spectinabilin also increased synaptic and cAMP-related transcripts and restored Rab3A and VAMP2 expression while normalizing stress-associated CREB phosphorylation. H89 prevented the recovery of CREB regulation and presynaptic proteins, indicating a requirement for PKA-associated signaling. Together, these findings identify spectinabilin as a marine-derived small-molecule scaffold that modifies Aβ42 assembly and preserves mitochondrial and synaptic homeostasis across cellular and C. elegans models.
Autophagy-modulating dermatological interventions include topical, intralesional and systemic therapies, defined bioactive molecules and nutraceutical candidates. Their effects are commonly evaluated using tissue-averaged LC3-II, p62/SQSTM1 and canonical pathway markers. Although these measures support assessment of autophagy pathway engagement, they may miss spatially restricted pharmacodynamic non-response and cannot determine whether persistent local dysfunction reflects inadequate exposure or biology-limited non-response. Here we propose spatial autophagy failure (SAF) as a spatial pharmacodynamic endpoint for autophagy-targeted dermatological interventions. SAF denotes contiguous skin domains showing evidence of impaired autophagic processing and lysosomal dysfunction relative to adjacent tissue. We use photoaged skin and melanophagy as the principal test case. In this setting, persistent hyperpigmented hotspots may partly reflect localized defects in melanosome clearance alongside altered melanogenesis and melanosome transfer. Chronic wounds and pathological scars provide additional dermatological settings in which spatially heterogeneous autophagic capacity may influence treatment response. SAF assessment integrates local drug exposure, local target or pathway engagement, autophagy-lysosome readouts and phenotype maps, distinguishing exposure-limited from biology-limited non-response. Treatment effects can be quantified using total SAF burden, largest-zone size (expressed as area in two-dimensional sections or volume in three-dimensional models), zone contiguity and distance to the nearest phenotype-associated region. These SAF-zone metrics may inform lead selection, formulation and route optimization, dose and schedule selection and pharmacodynamic monitoring. Together, these measurements reframe the central questions: Does an intervention merely shift autophagy markers on average? More importantly, does adequate local exposure produce local target or pathway engagement, restore autophagic processing and improve the corresponding local phenotype?
Intratumoral administration is widely used to achieve high local drug delivery while minimizing systemic toxicity. However, the fundamental assumption that locally injected agents remain within tumor tissue has rarely been quantitatively examined. Here, we show that drug leakage from the tumor surface can reduce leakage-adjusted local retention and limit therapeutic efficacy after intratumoral injection. Using multiple tumor models, conventional needle injection frequently resulted in drug escape from the tumor surface, leading to reduced leakage-adjusted retention and diminished therapeutic efficacy. Mechanical measurements revealed pronounced differences in tissue stiffness across tumor types, suggesting that tumor mechanical properties may contribute to differences in drug leakage and local retention. Histological analysis further showed that guided jet injection induces structural remodeling within tumor tissue, creating transient interstitial spaces that may facilitate intratumoral fluid propagation. Consistent with these structural observations, three-dimensional imaging demonstrated distinct cavity-formation patterns between conventional needle injection and guided jet delivery. Together, these findings indicate that drug leakage is an underrecognized physical limitation of intratumoral drug delivery and that tumor mechanical heterogeneity is associated with local retention. This study provides a rationale for improving local drug delivery through mechanically guided injection strategies.
Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by progressive inflammation and fibrosis. Left untreated, MASH can progress to cirrhosis, hepatocellular carcinoma, and liver failure. MASH has become the leading indication for liver transplantation worldwide. While global prevalence is increasing, effective and mechanism-oriented therapies remain limited. Based on earlier independent studies showing that lysosomes are impaired and autophagy is dysregulated in MASH, our aim was to finely map autophagy dysfunction in an experimental mouse model of MASH and explore the capacity of a modulator of chaperone-mediated autophagy to mitigate the course of the disease. We effectively identified a number of markers whose expression was pathologically increased or decreased in various autophagy pathways. In vivo, pharmacological modulation with the phosphopeptide P140 -currently evaluated in phase III-clinical trials for lupus- corrected the expression of some of these markers and restored lysosomal and mitochondrial autophagy programs. It reduced steatohepatitis and fibrosis, and improved systemic inflammatory features without, however, broadly correcting metabolic parameters. Mechanistically, consistent with its established HSPA8 interaction, P140 restored lysosomal/autophagy markers, supporting modulation of this proteostasis network. Our data indicate that this pharmacological restoration of lysosomal proteostasis engages key transcriptional regulators (Mediator complex), leading to the selective remodeling of pro-fibrotic and inflammatory pathways. Collectively, we identified a coordinated disruption of lysosomal quality control networks across multiple autophagy pathways in a validated mouse model of advanced MASH. We established lysosomal autophagy as a druggable vulnerability in MASH and support therapeutic repositioning of P140 as a safe strategy to counter progressive liver diseases.
Endoplasmic reticulum (ER) stress is triggered by several cellular perturbations causing protein misfolding, and activates the unfolded protein response (UPR), an initially adaptive signaling network that aims to restore ER and cellular homeostasis. Growing evidence indicates that UPR signaling extends beyond ER proteostasis, influencing mitochondrial function and bioenergetics through ER-mitochondria contact sites (ERMCs). The CHOP-ERO1A-IP3R axis has a primary role in recruiting mitochondria to adaptive UPR. However, its sustained activation renders UPR signaling maladaptive, leading to mitochondrial dysfunction through both outer mitochondrial membrane permeabilization (OMMP) and mitochondrial permeability transition pore (mPTP) opening, ultimately contributing to irreversible cell injury and disease pathogenesis. Here, we examine the molecular mechanisms that govern adaptive and maladaptive UPR signaling and discuss how these ER-centered responses impinge on mitochondrial and cellular physiology. We analyze three major drivers of coupling mitochondrial function to UPR signaling: (i) enhanced ERMCs, (ii) IP3R-mediated Ca²⁺ transfer from the ER to mitochondria, and (iii) bidirectional ROS/H₂O₂ exchange between the two organelles. We also discuss unresolved questions in the field and technological advances, including approaches to investigate ERO1-dependent redox nanodomains, ERO1 inhibitors and engineered ERMC linkers, that are advancing our understanding of ER-mitochondria crosstalk and revealing potential therapeutic opportunities. These insights may inform precision medicine strategies for diseases driven by chronic ER stress and mitochondrial dysfunction.
Splicing dysregulation frequently occurs in cancers, yet the functional implications of most mis-spliced genes remain elusive. Through a comprehensive pan-cancer analysis of splicing dysregulation, we identified universally mis-spliced genes in cancers and were surprised to find their significant functional enrichment in cell migration. Interestingly, the STE20-like protein kinase (SLK) gene encoding a scaffold protein showed a significant splicing shift from SLK-S to SLK-L isoforms across various cancer types. Detailed studies demonstrated this splicing shift promoted cancer metastasis in cellular and animal models. Mechanistically, RNA-binding Fox-1 Homolog 2 (RBFOX2) protein was identified as a splicing factor that regulates SLK splicing. The two isoforms interact with occludin with different affinities, contributing to their unique activities in cancer metastasis. Notably, the antisense oligonucleotides designed to suppress SLK-L splicing effectively inhibited cancer migration and invasion. Collectively, this study shows a new splicing switch with a key role in controlling cancer metastasis, shedding light on new cancer therapy via splicing manipulation.
Syncope and polypharmacy are prevalent in older adults and negatively affect quality of life. This study compares the impact of medication regimen complexity, the total number of medications per day as a measure of polypharmacy, and orthostatic hypotension (OH)-inducing drug burden in older adults with syncope. It also sought to determine a polypharmacy threshold warranting medication review and to identify a distinct polypharmacy phenotype among older adults with syncope and metabolic syndrome (MetS).This study included 104 patients presenting with syncope, stratified by age. Therapeutic complexity was measured using the Medication Regimen Complexity Index (MRCI), total number of medications per day, and an OH risk score (OHscore-SGLT2i). Older adults had significantly higher MRCI, total number of medications per day, and OHscore-SGLT2i than younger adults (p < 0.001), with the youngest-old and middle-old subgroups showing the highest therapeutic complexity (p < 0.05). Regression models adjusted for the comorbidity burden confirmed these findings. ROC analysis identified the total number of medications per day as the best discriminator (AUC = 0.841), with an optimal threshold of 3.5 medications. Notably, 85.7% of older adults with syncope and MetS exceeded this threshold (p < 0.001) and were significantly more likely to experience clinically significant polypharmacy with adverse outcomes (OR 18.9).Polypharmacy is the primary driver of therapeutic complexity in older adults with syncope. A threshold of four or more medications per day may prompt polypharmacy review, particularly in older adults with MetS, who may benefit most from targeted deprescribing.
Host-microbiota co-metabolism of tryptophan is increasingly recognized as a critical nexus linking diet, gut microbiota, immune function, serving as a core regulatory network governing cardiovascular function and systemic homeostasis. Its catabolism in vivo mainly proceeds through three distinct pathways: the kynurenine pathway, the serotonin pathway, and the gut microbiota-mediated indole pathway. Tryptophan metabolites exert multifaceted physiological and pathophysiological effects on the cardiovascular system via diverse specific receptors and non-receptor signaling pathways. Numerous clinical and basic studies have confirmed that the tryptophan metabolic network plays a dual role in the progression of cardiovascular diseases (CVDs), including atherosclerosis, myocardial ischemia/reperfusion injury, and heart failure. However, existing studies have largely focused on individual pathways or isolated metabolites, and an integrated, systematic view of the entire tryptophan metabolic network in CVDs remains lacking. This review summarizes the tryptophan metabolic pathways, the physiological effects of tryptophan metabolites including potential therapeutic targets, and their impacts on cardiovascular diseases. Furthermore, based on the complex pathophysiological regulatory mechanisms of tryptophan metabolism, we systematically elaborate therapeutic strategies including dietary intervention, gut microbiota modulation, and targeted pharmacological intervention against rate-limiting enzymes and core receptors. These multidimensional approaches hold promise for reshaping the tryptophan metabolic axis and providing novel therapeutic paradigms for the management and treatment of CVDs.
Kidney transplantation (KT) remains the optimal treatment for kidney failure, improving survival and quality of life. However, long-term graft outcomes have plateaued, largely due to transplant CKD and cardiovascular disease; agents such as mineralocorticoid receptor antagonists (MRAs) may help mitigate these risks. Mineralocorticoid receptor (MR) overactivation contributes to oxidative stress, inflammation, and fibrosis in both the heart and kidneys, suggesting a potential role for mineralocorticoid receptor antagonists (MRAs) in improving long-term patient and graft outcomes. Although evidence in KT is limited, MR blockade may offer clinical benefits by targeting aldosterone-mediated pathways. Proteinuria promotes sodium reabsorption in the aldosterone-sensitive distal nephron via epithelial sodium channels (ENaC), contributing to hypertension and volume overload. MRAs have been shown to reduce albuminuria and blood pressure in patients with diabetic nephropathy, even on background renin-angiotensin-aldosterone system (RAAS) blockade. The use of MRAs post-KT should be individualized, considering patient comorbidities and concomitant immunosuppressive therapy. While MRAs may provide cardiovascular and antiproteinuric benefits, the risk of hyperkalemia-though reduced with non-steroidal MRAs-must be carefully managed.
Bile acids, as cholesterol metabolites, orchestrate a regulatory network with mitochondrial quality control through nuclear receptor FXR, membrane receptor TGR5, and other signaling molecules, modulating mitochondrial biogenesis, dynamic equilibrium, selective autophagy, and redox homeostasis. TGR5 promotes PGC-1α-mediated mitochondrial biogenesis via the cAMP-PKA-CREB pathway, while concurrently regulating mitochondrial fission and calcium homeostasis through the PKCδ/Drp1 and GRP75-MAMs pathways. FXR, acting through transcriptional reprogramming and epigenetic mechanisms, governs fatty acid oxidation, antioxidant defense, and apoptotic pathways, and has been shown to restore PINK1/Parkin-dependent autophagy and suppress NLRP3 inflammasome activation in alcoholic liver disease. Noncanonical receptors, including S1PR2, VDR, and PXR, also participate in the regulation of mitochondrial dynamics and autophagy. Dysregulation of this network is closely associated with metabolic dysfunction-associated fatty liver disease, diabetic retinopathy, pancreatic β-cells injury, alcoholic liver disease, and sepsis-induced immunoparalysis. Agonists targeting the aforementioned receptors, such as INT-777, INT-767, and Fexaramine, have demonstrated the capacity to restore mitochondrial function and alleviate tissue damage in animal models. Future investigations should employ multi-omics and structural biology approaches to elucidate receptor crosstalk and concentration-dependent bidirectional effects, and to develop tissue-selective modulators, thereby facilitating clinical translation.
Small ubiquitin-like modifier (SUMO) conjugation, or SUMOylation, is a dynamic post-translational modification that regulates protein stability, localization, transcriptional activity, DNA damage response, and cellular stress adaptation. Increasing evidence indicates that dysregulated SUMOylation contributes to tumor progression, immune disorders, and neurodegenerative diseases, highlighting the SUMO pathway as a promising therapeutic target. However, despite extensive advances in SUMO biology, a comprehensive pharmacological assessment of SUMO pathway inhibitors, including their mechanisms of action, evidence quality, target engagement, and translational challenges, remains insufficient. This review presents an inhibitor-centered analysis of pharmacological strategies targeting the SUMOylation machinery. This review describes the molecular architecture of the SUMO conjugation cycle and identifies major druggable nodes, including the SUMO-activating enzyme (SAE), the SUMO-conjugating enzyme UBC9, SUMO-specific proteases (SENPs), and SUMO-dependent protein–protein interactions. It also examines the biological rationale for SUMO pathway inhibition in major disease contexts, with an emphasis on cancer, autoimmune disorders, and neurological diseases. Furthermore, SUMO pathway modulators are systematically classified according to their molecular targets and evidence maturity, including SAE inhibitors, UBC9-directed compounds, SENP inhibitors, direct SUMO binders, and natural product-derived modulators. Their mechanisms of action, biochemical potency, structural validation, cellular target engagement, in vivo efficacy, PK/PD properties, and developmental status are critically evaluated. Overall, this review provides a comprehensive pharmacological framework for understanding SUMO pathway inhibition and highlights key considerations for the development of next-generation SUMO-directed therapeutics.
Persistent disruption of the alveolar-capillary barrier (ACB) is the core pathological basis of acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF). ACB deterioration reflects a complex pathological process involving macrophage immunometabolic reprogramming, epithelial stress responses, and senescence-associated impairment of alveolar repair. Traditional single-target anti-inflammatory strategies are difficult to reverse this microenvironmental deterioration. Based on evidence from literature mining, network pharmacology, molecular docking, molecular dynamics (MD) simulations, protein conformational biology, and structure–activity considerations, this paper proposes selected flavonoid compounds as candidate "Targeted Structural Destabilizers." Rather than representing a universal class effect of all flavonoids, this hypothesis applies to structurally compatible compounds whose scaffold features, hydroxylation patterns, and target-interface compatibility may permit conformational perturbation of pathogenic hub proteins such as TP53 and STAT3. These compounds are hypothesized to shift selected hub proteins toward more flexible, partially destabilized, or molten globule-like conformational states, thereby attenuating pathological signaling outputs in a compound- and target-context-dependent manner. Functionally, this proposed mechanism may contribute to ACB repair by suppressing HIF-1/STAT3-associated inflammatory glycolysis in macrophages, supporting metabolic restoration, and modulating TP53-associated senescence-associated secretory phenotype (SASP) programs in alveolar epithelial cells. This review outlines a hypothesis-driven framework linking targeted structural destabilization, metabolic reprogramming, and anti-senescence repair. Direct biophysical, cellular, and disease-model validation will be required to determine whether this proposed flavonoid-based paradigm can be translated into effective ACB repair strategies.
Major depressive disorder remains unsatisfactorily addressed by monoaminergic antidepressants, and the search for mechanistically novel targets has converged on the immune system. Among these, the complement system offers a defined molecular route through which locally synthesized complement proteins may tag synapses for microglial engulfment. Preclinical studies implicate the C1q-C3-CR3 pruning axis and the anaphylatoxin receptors C3aR and C5aR in linking immune activation to region-dependent synaptic and neuroinflammatory changes, but causal evidence in patients remains absent. This review synthesizes genetic and pharmacological studies of C3, C3aR, and C1q in stress- and inflammation-based animal models; critically appraises the heterogeneous human biomarker and large-scale proteomic literature; and organizes candidate pharmacology into natural products and small molecules, established drugs with secondary complement-related actions, and clinical-stage complement inhibitors developed for other indications. We emphasize that no randomized controlled trial has tested deliberate complement inhibition in depression and that physiological complement functions, infectious risk, CNS delivery, regional heterogeneity, sex, and patient selection remain major barriers. Complement therefore represents a testable, biomarker-linked therapeutic hypothesis rather than an established treatment mechanism, requiring stratified trials with direct pharmacodynamic evidence.
