Search Results (2,601)

NHE3 is an essential Na+ transporter in the intestine, contributing to diarrhea associated with inflammatory bowel disease (IBD) or intestinal infections. Nevertheless, the influence of histone acetylation on intestinal NHE3 gene expression has not yet been investigated. Various methods were employed, including human intestinal epithelial cells (Caco2 cells), ex vivo mouse and human ileal enteroids, and in vivo mouse models, along with techniques such as real-time qPCR, Western blot, immunofluorescence staining, ChIP, and H3K27Ac HiChIP sequencing analyses. Our findings indicated that valproic acid (VPA, a class I HDAC inhibitor) significantly elevated both NHE3 mRNA and protein levels in IECs. ChIP and Chromatin accessibility assays revealed an enhanced enrichment of acetylated histones (H3/H4) and a more open chromatin state at the p-1329/p-541 region of the NHE3 promoter in Caco2 cells treated with VPA. HDAC2/3 inhibition by MI192 in Caco2 cells and mouse/human ileal organoids or siRNA knockdown of HDAC2 in Caco2 cells significantly increased NHE3 expression. Activation or ectopic overexpression of histone acetylase p300 in Caco2 cells increased NHE3 mRNA expression and enhanced accumulation of acetylated histone (H3) within the p-1329 to -161 bp region of the NHE3 promoter. Additionally, in vivo experiments revealed that VPA significantly increased NHE3 mRNA levels in the ileum and proximal colon of mice, along with increased NHE3 immunostaining. H3K27Ac HiChIP sequencing analysis of isolated IECs from the mouse ileum indicated that VPA increased H3K27Ac acetylation and facilitated chromatin looping between distal enhancers and the NHE3 promoter, thereby stimulating NHE3 transcription. In conclusion, HDAC2 inhibition and histone acetylation play pivotal roles in upregulating NHE3 expression, with therapeutic implications for inflammation-associated diarrhea linked to reduced NHE3 expression/function. Full article

Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small-cell lung cancer and is one of the leading causes of cancer-related deaths globally. Despite current developments, reliable biomarkers for effective diagnosis, prognosis, and patient stratification are still lacking. Methods: We analyzed publicly available TCGA-LUAD and GEO datasets using integrative bioinformatics approaches, including differential gene expression, weighted gene co-expression network analysis (WGCNA), survival modeling, mutation profiling, immune cell infiltration scores, machine learning, and bulk-RNA and single-cell RNA sequencing. Results: A total of 5581 deregulated genes were identified, with the turquoise module (298 genes) showing strong correlation with LUAD (Corr = −0.79, p < 2.2 × 10⁻³⁰⁸). The integration of two analyses yielded 281 overlapping genes, out of which nine candidates (ANO2, CHIAP2, CPED1, DNASE1L3, GSTM5, HTR3C, PRKCE, SLC14A1, and WNT3A) were selected via LASSO Cox regression to build a prognostic risk model. High-risk patients have significantly worse survival (log-rank p = 0.0027). CPED1 exhibited the highest mutation frequency, with 41% of TCGA-LUAD samples harboring mutations. Among all CPED1 mutation events, missense mutations were the most common (47%). GSEA and KEGG analysis revealed significant enrichment of pathways such as nucleocytoplasmic transport, oxidative phosphorylation, protein processing in the endoplasmic reticulum, ribosome, and ribosome biogenesis in high-risk patients. Immune infiltration analysis indicated differences in immune cell infiltration scores between high- and low-immune-score groups, with M1 macrophages showing strong statistical correlation with aDC, monocytes, and CD4⁺ naïve T cells. Machine learning confirmed that the combined Enet+PLS model predicted CPED1 as a core predictor, and CPED1 was successfully validated in independent GEO datasets (GSE43458 and GSE31210), showing strong diagnostic accuracy (AUCs up to 0.98). Finally, single-cell RNA sequencing revealed that CPED1 was mostly expressed in fibroblasts and myeloid cells, with CPED1 significantly downregulated in LUAD compared with normal samples. Conclusions: This study integrates multi-omics and machine learning to highlight CPED1 as a promising candidate biomarker, with potential diagnostic and prognostic relevance in LUAD. The nine-gene risk signature stratified patients by survival outcomes in the TCGA cohort. Genomic and immune analyses revealed features associated with the high-immune-score group. As the study is entirely computational and the prognostic model lacks external survival validation, these findings should be regarded as preliminary and hypothesis-generating, requiring future independent validation and functional studies to confirm the biological significance and clinical utility of CPED1 and related genes. Full article

Acute inflammatory challenge can impair intestinal barrier function and bile acid homeostasis in weaned piglets. Glutamate serves as an important energy substrate and functional amino acid for intestinal epithelial cells, yet the epitranscriptomic mechanisms underlying its potential protective effects remain poorly defined. This study investigated whether dietary glutamate supplementation is associated with m⁶A-dependent regulation of SLC10A2 and bile acid signaling in weaned piglets subjected to an acute LPS challenge, with supporting validation in IPEC-J2 cells. LPS challenge (100 μg/kg body weight) impaired ileal morphological structure, activated the TLR4/NF-κB signaling pathway, and aggravated intestinal inflammatory responses in piglets. In contrast, glutamate supplementation was associated with restored ileal mucosal morphology, up-regulated expression of intestinal tight junction proteins, and suppressed TLR4/NF-κB pathway activation. Further metabolomic analysis indicated that LPS stimulation and glutamate intervention altered ileal bile acid metabolism: LPS decreased total bile acid (TBA) content in ileal tissue while increasing TBA accumulation in ileal chyme, whereas glutamate treatment partially reversed this pattern, by elevating ileal tissue TBA and reducing chyme TBA, suggesting a facilitatory effect of glutamate on intestinal bile acid reabsorption. Glutamate supplementation was also associated with increased ileal ASBT (SLC10A2) and FXR (NR1H4) expression. The SLC10A2 transcript exhibited detectable m⁶A modification; glutamate supplementation rescued the LPS-induced downregulation of m⁶A demethylases FTO and ALKBH5, which was associated with reduced global and SLC10A2-specific m⁶A modification. In vitro experiments in IPEC-J2 cells suggested that inhibition of FTO or glutamate dehydrogenase attenuated the effects of glutamate on m⁶A modification and SLC10A2 expression, and that YTHDF2 may contribute to the degradation of hyper-m⁶A-modified SLC10A2 mRNA. Glutamate-derived α-KG may serve as a cofactor supporting demethylase expression and activity after LPS stimulation. Collectively, these findings suggest that glutamate may alleviate LPS-induced intestinal inflammation in weaned piglets through a pathway involving α-KG-dependent maintenance of m⁶A demethylase expression, reduced m⁶A modification of SLC10A2, and preserved ASBT/FXR signaling. This study provides evidence for a nutritional–epitranscriptomic axis that may contribute to intestinal protection under acute inflammatory stress. Full article

Background/Objectives: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have recently gained attention for their potential anticancer properties. However, their effects in bladder cancer remain poorly understood. In this preliminary study, we assessed the effects of canagliflozin, dapagliflozin, and empagliflozin on metabolic activity, cell cycle distributions, migratory behavior, and SGLT2 expression in the human bladder cancer cell line T24. Methods: Cellular metabolic activity, cell cycle distribution, apoptosis and necrosis, migration, and SGLT2 protein expression were assessed using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, wound-healing and single-cell migration assays, Western blotting, and fluorescence microscopy. Bioinformatic analyses of SLC5A2 were additionally performed. Results: All three compounds reduced MTT-derived metabolic activity in a concentration-dependent manner and induced G0/G1 cell-cycle accumulation without increasing apoptosis or necrosis after 24 h. Flozins also impaired collective wound closure and altered single-cell migration parameters, although replicate-level analysis showed no significant differences between individual treatment conditions and control after multiple-comparison correction. SGLT2 protein was detected in T24 cells and decreased following treatment, with compound-dependent differences in magnitude. Conclusions: Flozins affect metabolic activity, cell-cycle progression, wound closure, and migratory behavior in T24 cells. However, these findings do not establish SGLT2-specific mechanisms and were obtained at concentrations exceeding typical clinical plasma exposure. Further target-validation and mechanistic studies are required. Full article

Background/Objects: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline. Although Nrf2 is a key regulator of oxidative stress in AD, the molecular factors associated with Nrf2 signaling and their potential regulatory relationships remain incompletely understood. This study aimed to systematically identify and validate a novel Nrf2-associated signaling axis in AD. Results: Slc2a1 was identified as a key Nrf2-associated candidate gene. In the SCOP-induced AD model, reduced Nrf2 expression was accompanied by decreased Slc2a1 expression, cognitive impairment, hippocampal neuronal injury, excessive ROS accumulation, and mitochondrial abnormalities. Pharmacological modulation of Nrf2 was associated with corresponding changes in Slc2a1 expression, while Nrf2 activation was accompanied by improvements in oxidative stress and neuronal injury. Conclusions: This study identifies a potential functional relationship between Nrf2 signaling and Slc2a1 expression in AD-related pathology and proposes the Nrf2/Slc2a1 pathway as a potential mechanistic framework linking oxidative stress to mitochondrial abnormalities. Full article

Background: Prostate cancer (PC) is a heterogeneous disease in which the histopathological grade does not always reflect underlying biological behavior. While transcriptomic studies have provided insight into tumor biology, grade-associated molecular changes remain incompletely defined, particularly in underrepresented populations such as those from the Middle East and North Africa (MENA) region. Methods: In this study, we used a pathology-guided transcriptomic approach to examine gene expression patterns across PC grades in a MENA cohort. RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) tissues, including benign prostatic hyperplasia (BPH, n = 7), low-grade tumors (Gleason 6–7 [3 + 4]; LG; n = 7), and high-grade tumors (Gleason 7 [4 + 3]–10; HG; n = 7). Differential expressions, pathway-level enrichment analyses and the estimation of immune cell composition were carried out, followed by comparison with publicly available datasets (TCGA-PRAD, n = 496), including LG tumors (n = 292) and HG tumors (n = 204), using the GEPIA2 and UALCAN platforms. Selected genes were further assessed using qRT-PCR in an independent set of samples (n = 21). Representative immunohistochemical images from the Human Protein Atlas were reviewed to provide descriptive protein-level context across tumor grades. Results: Transcriptomic comparisons of tumor samples with benign controls identified a set of shared transcriptional changes present in both low- and high-grade disease. Among these, SLC29A2 and IL2RA showed consistent upregulation across tumor grades and similar expression trends in external datasets. Direct comparison between HG and LG tumors revealed distinct transcriptional profiles with patterns indicative of increased proliferative activity and altered immune-related signaling in higher-grade disease. Pathway-level analyses showed the enrichment of cell-cycle and metabolic gene signatures in HG tumors, whereas inflammatory and NF-κB-associated transcriptional signatures showed a comparatively reduced expression. Additional genes, including AAMDC, ASAH2, TNFRSF1B, NFKBIL1, and NFKBIZ, were associated with these grade-dependent differences. qRT-PCR findings were generally consistent with the RNA-seq results for selected targets. Conclusions: This study describes transcriptional patterns associated with the PC grade in a MENA cohort using a pathology-guided framework. The findings highlight candidate genes associated with tumor presence and grade progression and provide a foundation for further investigation in larger, well-annotated cohorts, particularly in populations that remain underrepresented in transcriptomic studies. Full article

Metabolic syndrome (MetS) is associated with ectopic fat deposition, chronic systemic inflammation, oxidative stress, and increased susceptibility to organ dysfunction. While its cardiovascular consequences have been extensively studied, pulmonary al-terations remain less well characterized, particularly with respect to ferropto-sis-regulatory pathways. In this study, we evaluated ectopic fat deposition, TLR4/NF-κB signaling pathway, and ferroptosis-regulatory markers in a MetS rat model and analyzed the therapeutic potential of combined resveratrol plus quercetin (combined R + Q) supplementation. Rats were maintained for five months with 30% sucrose in drinking water to induce MetS and subsequently treated for 4 weeks with the R + Q combination (50 and 0.95 mg/kg/day, respectively). Lung tissue was analyzed by fluorescence microscopy to assess fat deposition, by colorimetric histology to evaluate hemosiderin-containing cells, including the quantification of hemosiderin-laden macrophages (HLMs), and by immunoblotting to determine TLR4, p-p65, and glutathione peroxidase 4 (GPX4), as well as cystine/glutamate antiporter SLC7A11 (xCT) protein expression. Lungs from MetS rats exhibited significantly higher fat deposits, pathological HLMs accumulation, upregulated TLR4/p-p65 signaling, elevated compensatory GPX4 expression, and depressed xCT levels compared with controls. Notably, the combined R + Q treatment markedly attenuated alterations in TLR4/NF-κB signaling and successfully restored xCT expression (p = 0.0116), stabilizing pulmonary redox homeostasis and limiting overall tissue susceptibility to lipotoxic injury. Full article

Chemotherapy-induced neurotoxicity, affecting both the central and peripheral nervous systems, is a frequent and severe adverse effect of paclitaxel (PAC) treatment with limited therapeutic options. We previously demonstrated that PAC triggers neuronal cell death via ferroptosis. αO-Conotoxin GeXIVA[1,2], a marine-derived peptide, has shown efficacy in alleviating chemotherapy-induced neuropathic pain. In the present study, we investigated whether GeXIVA[1,2] protects neurons from PAC-induced neurotoxicity by suppressing ferroptosis. Using SH-SY5Y and HT-22 neuronal cell lines, we found that GeXIVA[1,2] pretreatment rescued PAC-impaired cell viability without exhibiting cytotoxicity. GeXIVA[1,2] markedly attenuated PAC-induced reactive oxygen species (ROS) overproduction and restored intracellular glutathione (GSH) levels. Mechanistically, PAC suppressed the Nrf2/SLC7A11/GSH/GPX4 ferroptosis-defense pathway, and GeXIVA[1,2] reactivated this axis by upregulating Nrf2, SLC7A11, and GPX4 protein expression. These results reveal a novel ferroptosis-suppressive function of GeXIVA[1,2] in the context of PAC-induced neurotoxicity. Our findings provide a mechanistic foundation for developing GeXIVA[1,2] as a ferroptosis-targeted intervention against chemotherapy-induced neurotoxicity. Full article

Glycogen storage disease Ib (GSD Ib) is an ultra-rare metabolic disease caused by variants in the SLC37A4 gene affecting activity of the glucose-6-phosphate transporter (G6PT). G6PT mediates transport of glucose-6 phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, thereby playing a key role in glucose homeostasis. To date, no approved therapies directly restore G6PT function, highlighting a major unmet need. Pharmacological chaperone (PC) therapies, including those targeting membrane transporters, are a known and clinically employed therapeutic strategy. The efficacy of PC therapy is highly dependent on the underlying pathogenic variant. While certain missense variants may respond favorably, particularly those associated with protein misfolding and residual function, null variants are generally considered unsuitable targets due to the absence of a protein that could be rescued. To the best of our knowledge, no previous review has systematically examined the global landscape of SLC37A4 variants. The aim of this review was to collect the spectrum and frequency of SLC37A4 variants reported worldwide and connect them with all available structural and functional data. In 425 GSD Ib patients, we found that approximately 10% of all variants are strong PC candidates and 14–30% are reasonable but lower-confidence candidates (other missense non-deactivating variants), while the rest are poor PC candidates (substrate-pocket variants) and null variants (nonsense, frameshift and splicing). Although functional studies are required to definitely validate PC-responsive missense variants in the SLC37A4 gene, our review suggests, for the first time, the existence of a minimal threshold at which a PC approach may become clinically relevant for GSD Ib patients. Full article

Background: Myelodysplastic neoplasms (MDSs) are clonal hematopoietic stem cell disorders associated with ineffective hematopoiesis, chronic inflammation, and increased cardiovascular morbidity. Although metabolic dysregulation has been implicated in MDS pathogenesis, systemic metabolic alterations remain incompletely characterized. Methods: Plasma samples from treatment-naïve patients with MDS or chronic myelomonocytic leukemia (CMML) and age-matched healthy controls were analyzed using quantitative nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Metabolomic profiles were compared using unsupervised and supervised multivariate analyses, validated in an independent external MDS cohort, and integrated with re-analysis of publicly available RNA-sequencing datasets from purified CD14⁺ CMML monocytes. Results: Patients with MDS and CMML exhibited broad reductions in circulating lipoprotein-associated metabolites, including HDL-, LDL-, IDL-, and apolipoprotein-associated fractions, indicating disturbed systemic lipoprotein homeostasis. Within the discovery cohort, CMML samples showed higher concentrations of the ketone bodies 3-hydroxybutyrate and acetoacetate, as well as succinate. LC-MS analysis demonstrated selective increases in C18:1 acylcarnitine, oleic and isopalmitic acids, whereas free carnitine abundance remained unchanged. Elevated 3-hydroxybutyrate levels were not associated with mutational burden, hematologic parameters, disease risk, or immunophenotypic features. Re-analysis of public CMML monocyte transcriptomes demonstrated increased expression of genes involved in lipid uptake and intracellular lipid trafficking, including FABP5, APOE, LPL, and SLC27A2, without coordinated activation of fatty acid oxidation pathways. External cohort analysis confirmed the overall MDS-associated plasma metabolomic profile. Conclusions: MDSs and CMML are associated with reproducible alterations in systemic lipid metabolism characterized by reduced circulating lipoprotein-associated metabolites, while CMML showed more pronounced ketone body- and acylcarnitine-associated metabolic phenotype accompanied by changes in lipid-handling transcriptional programs. These findings support altered systemic lipid metabolism and carnitine-dependent fatty acid handling as characteristic features of myeloid neoplasms and provide a rationale for future functional studies investigating lipid metabolism in disease pathogenesis. Full article

High-intensity interval training (HIIT) is widely recognized as an effective strategy for improving cardiorespiratory fitness and metabolic health. Beyond these physiological benefits, growing evidence indicates that HIIT may also induce beneficial immunometabolic adaptations. A key exercise-responsive metabolite in this context is lactate, which is increasingly being recognized not as a metabolic waste product but as a bioactive signaling metabolite capable of coordinating metabolic, inflammatory, and immune processes. This narrative review examines current evidence suggesting a potential role for exercise-induced lactate in immune responses associated with HIIT. We summarize the molecular pathways through which lactate may interact with immune cells, including uptake via monocarboxylate transporters (MCT1/MCT4) and SLC5A12, receptor-dependent signaling through GPR81/HCAR1, and epigenetic regulation via histone lactylation. We further discuss the cell-specific effects of lactate on macrophages, dendritic cells, neutrophils, and T lymphocytes, highlighting how these mechanisms may influence immune-cell metabolism, inflammatory regulation, and functional remodeling. A central concept emerging from the current literature is that the biological actions of lactate are highly dependent on the kinetics, duration, and physiological context of exposure. Unlike pathological lactate elevations observed in conditions such as cancer, sepsis, or mitochondrial myopathies—the latter potentially involving an exaggerated lactate response during exercise due to impaired oxidative metabolism—HIIT generates transient systemic lactate elevations as part of a coordinated neuroendocrine and metabolic response. When combined with adequate recovery, these repeated metabolic perturbations may promote hormetic adaptations characterized by improved inflammatory regulation, enhanced immune resilience, and more efficient immunometabolic homeostasis. Conversely, excessive training loads or inadequate recovery may shift these responses toward maladaptive immune stress. Overall, current evidence suggests a paradigm shift in exercise immunology in which lactate should be regarded as one component of an integrated immunometabolic signaling network rather than simply as a marker of anaerobic metabolism. Future mechanistic studies integrating lactate kinetics, immune-cell phenotyping, transporter expression, and lactate-dependent post-translational modifications are needed to clarify the extent to which lactate may contribute to exercise-induced immune remodeling and to guide the development of immunologically informed HIIT protocols. Full article

Mutations in SLC26A4, which encodes the anion transporter pendrin, represent one of the most common genetic causes of hereditary hearing loss, including Pendred syndrome and DFNB4. Pendrin plays a critical role in maintaining ion homeostasis within the inner ear, particularly in the endolymphatic sac (ES), making it an important therapeutic target for gene replacement strategies. However, efficient delivery of therapeutic genes to relevant inner ear structures remains a major challenge for clinical translation. In this study, we evaluated the inner ear transduction profile of AAV8BP2, an engineered AAV8-derived capsid, in comparison with AAV2.7m8 and AAV8 in mice. Neonatal mice received posterior semicircular canal (PSCC) injections at postnatal day 0 (P0), and viral transduction in the cochlea and ES was assessed at P7. To examine age-dependent differences in viral transduction, additional experiments were performed in adult mice injected at P21 and analyzed at P28. We also compared three surgical delivery routes for inner ear gene transfer: PSCC injection, round window membrane (RWM) injection, and RWM injection combined with PSCC fenestration. AAV8BP2 effectively transduced the ES in both neonatal and adult mice and showed greater GFP expression in the spiral prominence than AAV8 following neonatal administration. Among the three delivery routes evaluated in adult mice, PSCC injection achieved the highest ES transduction while maintaining cochlear hair cell transduction comparable to that achieved with RWM-based approaches. Together, these findings define the relative transduction profiles of the tested AAV capsids and delivery routes and provide a basis for selecting vector-delivery route combinations for SLC26A4-targeted inner ear gene therapy. Full article

Cigarette smoke exposure is a major preventable risk factor for respiratory disease and drives oxidative and inflammatory lung injury, highlighting the urgent need for safe, multi-target interventions beyond conventional anti-inflammatory therapy. Formononetin (FMN), a naturally occurring isoflavone with antioxidant, anti-inflammatory, and microbiota-modulating potential, may offer a dietary-botanical strategy against smoke-related pulmonary damage. This study evaluated FMN against cigarette smoke extract (CSE)-induced lung injury and explored its associations with intestinal barrier integrity, gut microbiota, taurine metabolism, SLC6A6 expression, and NF-κB activation. In a CSE-challenged mouse model, oral FMN, particularly at 70 mg/kg, improved body weight gain, reduced the lung index, attenuated pulmonary histopathological injury, restored GSH/GSSG and SOD, decreased MDA, and suppressed TNF-α, IL-1β, and IL-6 expression. FMN also ameliorated colonic injury and restored ZO-1 and occludin expression. Exploratory 16S rRNA sequencing and fecal metabolomics indicated FMN-associated alterations in gut microbial composition and metabolic profiles, with taurine and hypotaurine metabolism identified as a candidate pathway for further investigation. FMN further restored lung taurine content and SLC6A6 expression while inhibiting NF-κB activation. These findings suggest that FMN alleviates CSE-induced lung injury and that this improvement is associated with coordinated changes in gut microbiota composition, taurine metabolism, SLC6A6 expression, and NF-κB activation. Full article

Oxidative stress drives skin aging, barrier impairment, and inflammatory amplification, making dietary antioxidants potential systemic contributors to cutaneous redox homeostasis. Edible fungi are distinctive sources of redox-active metabolites, particularly ergothioneine, a stable sulfur-containing antioxidant whose cellular uptake is mediated by the ergothioneine transporter OCTN1 (SLC22A4). This review evaluates ergothioneine, polysaccharides and β-glucans, cordycepin, phenolics, and Ganoderma triterpenoids as processing-sensitive dietary bioactives with redox relevance rather than topical cosmetic ingredients. We examine how cultivation, drying, cooking, extraction, fermentation, and microbial biomanufacturing determine antioxidant formation, retention, oral bioaccessibility, and dose realism, and how antioxidant response, inflammatory, mitochondrial, and gut microbiota-mediated pathways connect intake to skin endpoints. The strongest oral evidence concerns biomarker-linked ergothioneine-rich Pleurotus. Smaller Flammulina velutipes and Sparassis crispa trials report hydration or transepidermal water loss signals without comparable exposure biomarkers, whereas purified ergothioneine provides provisional non-mushroom food evidence. Compared with better-established oral ingredients, edible fungi offer distinctive food technology advantages but a narrower human evidence base. Priorities include processing-aware quality and safety markers, contaminant control, standardized digestion models, dose-realistic exposure estimates, and biomarker-anchored randomized human trials. Full article

This study investigates a simulation-based estimation–control chain that integrates an interactive multiple model adaptive unscented Kalman filter (IMM-AUKF) with a multiple-input multiple-output model predictive controller (MIMO-MPC). A seven-degree-of-freedom vehicle model and a Pacejka tire model are used to represent nonlinear vehicle dynamics. The controller updates model and regression region steering constraints from the estimated adhesion state and jointly allocates front/rear steering and longitudinal force commands. The revised experiments use a 0.5 ms plant integration step and a consistent 20 ms estimator/controller update. Under high-adhesion double lane change (DLC), the proposed chain lowers speed RMSE from 0.7950 to 0.1833 m/s and mean adhesion estimation RMSE from 0.1567 to 0.0812. Under variable-adhesion single lane change (SLC), lateral RMSE decreases from 0.1816 to 0.1649 m, speed RMSE from 0.7983 to 0.2505 m/s, and mean adhesion estimation RMSE from 0.1622 to 0.0949. Heading error is not uniformly improved and is reported as a design trade-off. These results provide reproducible simulation evidence, while hardware-in-the-loop and real-vehicle validation remain future work. Full article