Current therapies for diabetic kidney disease (DKD) slow progression but fail to halt irreversible renal fibrosis, largely because early pathogenic drivers are overlooked. While endothelial glycocalyx disruption is recognized as an initiator of albuminuria, existing literature lacks a unified model connecting this initial barrier loss to the full fibrotic cascade. This review systematically integrates the molecular networks driving glycocalyx degradation, specifically detailing the synergistic interplay among oxidative stress, sheddase activation, and the AGEs/RAGE/NF-κB axis. Unlike previous reviews, we explicitly map how the shedding of core components-such as Syndecans and Glypicans-triggers downstream leukocyte adhesion via the intracellular MyD88/NF-κB pathway, actively propagating renal inflammation and exacerbating the progression of renal fibrosis. By redefining glycocalyx damage as a critical pathological amplifier that actively drives glomerular filtration barrier disruption and subsequent inflammatory and fibrotic cascades, rather than a passive structural consequence of hyperglycemia, we expose critical gaps in standard DKD management. We further critically evaluate the clinical viability of emerging glycocalyx-targeted strategies, highlighting specific applications for early diagnostic biomarkers and addressing current challenges in targeted drug delivery, ultimately providing a precise roadmap for preventing DKD progression.

The immune system relies on a delicate equilibrium between activation and suppression to sustain homeostasis, and the disruption of this balance is a central feature in the pathophysiology of liver diseases. Among the key regulators of this process are T follicular helper (TFH) and T follicular regulatory (TFR) cells, which orchestrate B cell responses through reciprocal functions. TFH cells promote B cell differentiation, antibody production, and memory formation, whereas TFR cells suppress TFH and B cell activity, collectively acting as guardians of immune balance. The liver, which is the body's main organ for filtering blood, is especially vulnerable to pathogen- and damage-associated molecular patterns. Excessive immune activation in this context can drive hepatocyte injury, inflammation, fibrosis, and ultimately immune exhaustion. Alterations in the number and functionality of TFH and TFR cells, alongside their associated cytokine milieu, have been increasingly recognized across diverse liver diseases and with their pathogenesis. Different etiologies of liver disease, ranging from viral hepatitis and alcohol-related injury to autoimmune and genetic causes, present with distinct clinical and pathological features. Yet, a common thread is the dysregulated immune profile, where deviations in TFH and TFR dynamics represent both convergent and disease-specific patterns. A deeper understanding of their functional roles across different disease states offers predictive insight into liver-associated immune complications. This narrative review highlights a current understanding of TFH and TFR cells in liver disease, emphasizing their impact on progression, value as biomarkers, and therapeutic potential, while outlining how their regulatory balance informs disease mechanisms and treatment approaches.

Interleukin-18 (IL-18) is a pleiotropic cytokine that promotes interferon-γ (IFN-γ) production and cytotoxicity in natural killer (NK) and T cells, but its antitumor activity is limited by ligand maturation and release, IL-18-binding protein (IL-18BP) sequestration, IL-18 receptor (IL-18R) abundance and signaling competence, exposure kinetics, and the tumor microenvironment. This regulatory network may explain the limited and heterogeneous objective responses observed in early clinical studies of recombinant human IL-18 (rhIL-18). Here, we review strategies for engineering the IL-18-IL-18BP axis for cancer immunotherapy, including decoy-resistant IL-18 (DR-18) variants, IL-18R agonists and mimetics, oncolytic virus (OV)-mediated delivery, IL-18-armored adoptive cell therapies (ACT), membrane-tethered IL-18, and combinations with immune checkpoint blockade (ICB). Preclinical studies support intratumoral immune activation and tumor control, whereas early clinical studies of IL-18-armored cellular therapies highlight cytokine release syndrome (CRS), prolonged cytopenias, and systemic inflammation as major safety concerns. Accordingly, clinical development should evaluate target engagement, antitumor activity, and safety as distinct dimensions, integrating free and IL-18BP-bound IL-18, IL-18R expression, downstream signaling competence in effector cells, spatial immune contexture, and inflammatory toxicity. Conditional or tumor-restricted activation, controllable expression, and exposure profiles matched to tumor biology may be required to establish a clinically manageable therapeutic window for IL-18-based immunotherapy.

Mitochondrial morphology dynamics are essential for neuronal function and are regulated by fission and fusion machinery, in which the actin cytoskeleton plays a crucial role. Coactosin-like F-actin-binding protein 1 (Cotl1), a key component of the actin cytoskeleton, is gaining attention for its profound pathophysiological implications in human neurodegenerative disorders. However, its role in neuronal function remains unclear. Therefore, we aimed to explore the role of Cotl1 in mitochondrial morphology and neuronal dysfunction. We generated Cotl1-knockdown and Cotl1-K75E mutants to examine mitochondrial structure and produced Cotl1-knockout (Cotl1[-/-]) mice to assess learning and memory-related phenotypes. Both Cotl1 knockdown and Cotl1-K75E overexpression induced mitochondrial elongation and disrupted F-actin organization by inhibiting fission. In silico analysis of differentially expressed genes in Cotl1[-/-] hippocampal tissue revealed a link between Cotl1 and neuronal function. Cotl1[-/-] mice further exhibited impaired learning and memory, accompanied by decreased doublecortin (Dcx) expression in the hippocampal dentate gyrus (DG). Notably, restoration of Cotl1 expression in the DG recovered both Dcx expression and cognitive functions. These results highlight the crucial role of Cotl1 in mitochondrial fission through its regulation of F-actin and Drp1 assembly in the mitochondria, and they link Cotl1 loss to impaired learning and memory and to reduced Dcx expression in the hippocampal DG. Collectively, these findings suggest an important role of Cotl1 in maintaining developing granule neurons in the dentate gyrus, a process closely linked to mitochondrial fission and cognitive function.

Diabetic retinopathy (DR) is a leading cause of visual impairment and is characterized by progressive microvascular injury, neurovascular dysfunction, and sustained oxidative stress. Lactylation, a lactate-derived post-translational modification, may represent a mechanistic link between hyperglycemia-induced metabolic reprogramming and epigenetic regulation. In the diabetic retina, enhanced glycolysis and lactate accumulation promote aberrant histone and non-histone lactylation, thereby contributing to endothelial dysfunction, Müller cell activation, inflammatory cell death, ferroptosis, and pathological angiogenesis. These processes may amplify oxidative injury by reshaping inflammatory and angiogenic transcriptional programs, impairing antioxidant defenses, and disrupting mitochondrial homeostasis. This review synthesizes direct retinal evidence linking lactylation to DR-related phenotypes, evaluates redox-related findings from retinal and other diabetic complications, and discusses the emerging but not yet established relationship between lactylation and oxidative stress in DR.

The increasing global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the need for effective treatment strategies. This study investigated the combined effects of empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and curcumin (Cur), a natural polyphenol, on MASLD development in mice. Male C57BL/6J mice were fed a normal chow diet (NCD) or a high-fat diet (HFD) for 23 weeks. HFD-fed mice received EMPA, Cur, or their combination throughout the dietary intervention. Markers of lipid metabolism, thermogenesis, and oxidative stress were evaluated. In vivo adipose tissue browning was assessed via [18]F-FDG PET/CT imaging. Co-administration of EMPA and Cur significantly attenuated body weight gain (p < 0.001 vs. HFD) and adipose tissue expansion without altering food intake. Glucose tolerance and hepatic AKT phosphorylation were markedly improved (p < 0.001). Hepatic TG content and MASLD Activity Score were substantially reduced (p < 0.001), accompanied by AMPK activation, FAS suppression, and CPT1A upregulation. Fecal TG content was elevated with combination treatment (p < 0.001 vs. HFD), indicating reduced intestinal lipid absorption. BAT thermogenic activity, confirmed by [18]F-FDG PET/CT and cold tolerance testing, and sWAT browning were most pronounced in the combination group. Hepatic oxidative stress markers were most improved by the combination, accompanied by Nrf2 pathway activation. Co-administration of EMPA and Cur represents a multi-target approach for mitigating MASLD development. This effect entails comprehensive improvement of metabolic homeostasis, reduced hepatic steatosis, and increased systemic energy expenditure. Formal combination interaction analysis indicated synergistic effects across key metabolic endpoints.