Solute Carrier Research Articles

CMSP exerts anti-tumor effects on small cell lung cancer cells by inducing mitochondrial dysfunction and ferroptosis

Abstract Purpose This study aims to investigate the role and mechanism of p-hydroxyl cinnamaldehyde (CMSP) in triggering ferroptosis of small cell lung cancer (SCLC) cells. Methods The impact of CMSP on ferroptosis in H1688 and SW1271 cells was assessed through cell experiments and biological information analysis. Moreover, the expression of heme oxygenase 1 (HMOX1) in SCLC tissue was examined. Results Following CMSP treatment, a concentration-dependent increase in cell death was observed, and differentially expressed genes were found to be associated with ferroptosis. CMSP notably facilitated ferroptosis events, such as elevated levels of reactive oxygen species (ROS), Fe2+, malondialdehyde (MDA), transferrin receptor 1 (TFR1), divalent metal transporter 1 (DMT1), and decreased levels of glutathione (GSH), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4). Furthermore, CMSP promoted mitochondrial dysfunction, manifested as reduced mitochondrial volume, increased membrane density, elevated mitochondrial ROS, and decreased mitochondrial membrane potential. Consistently, the mitochondrial-targeted antioxidant Mito-TEMPO reversed CMSP-induced ferroptosis. Expression of the HMOX1 gene was markedly increased under CMSP treatment, while lower expression was observed in cancer tissue compared to adjacent tissue. Conclusion CMSP triggers mitochondrial dysfunction via HMOX1 activation, leading to ferroptosis in SCLC cells, underscoring its potential as a therapeutic agent for SCLC.

Investigation into the influence of mild hypothermia on regulating ferroptosis through the P53-SLC7A11/GPX4 signaling pathway in sepsis-induced acute lung injury

BackgroundSepsis-induced acute lung injury (S-ALI) significantly contributes to unfavorable clinical outcomes. Emerging evidence suggests a novel role for ferroptosis in the pathophysiology of ALI, though the precise mechanisms remain unclear. Mild hypothermia (32–34 °C) has been shown to inhibit inflammatory responses, reduce oxidative stress, and regulate metabolic processes. P53 has been reported to downregulate the transcriptional activity of solute carrier family 7 member 11 (SLC7A11), thereby limiting cystine uptake. This reduction in cystine availability compromises the activity of Glutathione peroxidase 4 (GPX4), a cystine-dependent enzyme, ultimately increasing cellular susceptibility to ferroptosis. However, it remains unclear whether mild hypothermia exerts protective effects through the P53-SLC7A11/GPX4 signaling pathway. This study investigates the influence of mild hypothermia on ferroptosis mediated by the P53-SLC7A11/GPX4 pathway in S-ALI.MethodsThis study utilized both in vivo and in vitro models. In the vivo model, 64 Sprague–Dawley rats were employed, with 40 analyzed for survival outcomes. Sepsis was induced using the cecum ligation and puncture (CLP) method, after which rats were subjected to either normothermic (36–38 °C) or mild hypothermic (32–34 °C) conditions for a duration of 10 h. Twelve hours post-surgery, blood samples, bronchoalveolar lavage fluid, and lung tissue samples were harvested for histological analysis, measurement of inflammatory markers, wet/dry ratios, blood gas analysis, assessment of oxidative stress and ferroptosis, Western blotting, and RT-qPCR analysis. In the in vitro model, RLE-6TN cells were exposed to lipopolysaccharide (LPS) for 24 h under normothermic and mild hypothermic conditions. These cells were then evaluated for cell viability, inflammatory markers, oxidative stress levels, ferroptosis markers, as well as Western blot and RT-qPCR analyses.ResultsCLP-induced sepsis led to elevated levels of inflammatory markers, increased lung injury scores, and heightened oxidative stress markers. These detrimental effects were significantly ameliorated by mild hypothermia. Furthermore, mild hypothermia reversed the modified expression of P53, SLC7A11, and GPX4 signaling molecules. Notably, mild hypothermia also improved the 5-day survival rate of CLP rats.ConclusionMild hypothermia attenuates S-ALI and modulates ferroptosis through the P53-SLC7A11/GPX4 signaling pathway.

H3K14la drives endothelial dysfunction in sepsis‐induced ARDS by promoting SLC40A1/transferrin‐mediated ferroptosis

AbstractPulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis‐induced ARDS remains unclear. Integrative lactylome and proteome analyses were performed to identify the global lactylome profile in the lung tissues of septic mice. Cut&Tag analysis was used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Septic mice presented elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was enriched at promoter regions of ferroptosis‐related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. For the first time, we reported the role of lactate‐dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis‐induced lung injury. Our findings suggest that manipulation of the glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis‐associated ARDS.

On the substrate turnover rate of NBCe1 and AE1 SLC4 transporters: structure-function considerations

A transport protein’s turnover rate (TOR) is the maximum rate of substrate translocation under saturating conditions. This parameter represents the number of transporting events per transporter molecule (assuming a single transport site) per second (s). From this standpoint, a transporter’s TOR is similar to an enzyme’s catalytic constant. Knowledge of a transporter’s TOR allows comparison of the transport capacity of various transporters at the molecular level as well as the total transport per cell and whole organ levels. Despite this, there is currently a very limited number of transporters, for which TOR has been determined experimentally. In the SLC4 transporter family of CO32−/HCO3− transporters, erythrocyte AE1 (eAE1; SLC4A1) is the only member, for which TOR has been determined (∼50,000 s−1). Whether other SLC4 family members have similar TOR values is currently unknown. Here we report TOR measurements of the electrogenic Na+-CO32− cotransporter NBCe1-A (SLC4A4) and the kidney specific AE1 splice variant, kAE1, that play important roles in renal bicarbonate absorption and are mutated in proximal and distal renal tubular acidosis respectively. We have also remeasured the eAE1 TOR value for comparison. NBCe1-A had a TOR value of ∼30,400 s−1 whereas kAE1 and eAE1 had significantly higher values (62,000 s−1 and 60,500 s−1 respectively). We modeled the inward-facing (IF) conformation of NBCe1-A to determine conformational changes during its transport cycle. Comparison of this IF model with our previously determined cryoelectron microscopy (cryoEM) outward-facing (OF) conformation structure, demonstrates that NBCe1-A has an elevator-type transport mechanism with a small vertical ∼5 Å shift of the ion coordination site as we have previously shown for AE1. We speculate that this very small vertical movement plays an important role in contributing to the very high TOR numbers of SLC4 transporters.

Effects of SCT genetic polymorphisms on methotrexate concentrations and toxicities in Chinese children with acute lymphoblastic leukemia

Solute carrier (SLC) transporters play a crucial role in facilitating the cellular uptake of various anticancer drugs, such as methotrexate (MTX). This study aimed to analyze the impact of nonsynonymous single nucleotide polymorphisms (SNPs) in SLC19A1, SLCO1B1, and SLCO1B3 on MTX exposure, toxicities, and prognosis in 148 patients with acute lymphoblastic leukemia (ALL). The SLCO1B3 rs7311358 polymorphism was significantly associated with the median dose-normalized MTX concentrations at 24 h (p < .05). There were significant differences in the proportions of patients with serum MTX levels >40 µmol/L at 24 h among SLC19A1 rs1051266 GG, GA, and AA genotype carriers (29.0, 24.7, and 6.2%, respectively, p < .05). The SLC19A1 rs1051266 G > A polymorphism also displayed significant associations with hematological (p < .05) and hepatic toxicities (p < .01). Our findings indicate that the analysis of SNPs in solute carrier transporters (SCTs) could offer valuable insights into the interpatient variability of MTX pharmacokinetics and toxicities in ALL children.

SLC7A11 suppresses pyroptosis to alleviate rheumatoid arthritis development by modulating the IL-17 pathway.

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. This study aims to explore the potential mechanisms by which solute carrier family 7 member 11 (SLC7A11) influences RA development. Collagen-induced arthritis (CIA) mice were constructed to observe disease onset and pathological scores. Pathological changes were examined using Hematoxylin-eosin and Safranin O-Fast Green staining. Levels of lactate dehydrogenase (LDH), inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-18 and IL-1β), and oxidative stress (reactive oxygen species, malondialdehyde, and glutathione) were measured using ELISA. Western blotting was performed to detect the expression of pyroptosis- and pathway-related proteins. Fibroblast-like synoviocytes of RA (RA-FLS) were treated with TNF-α. Cell migration, invasion, and Caspase-1 levels were assessed through scratch assays, Transwell assays, and flow cytometry, respectively. The correlation between SLC7A11 and immune cell infiltration in RA was analyzed using bioinformatics. Additionally, downstream pathways of SLC7A11 in RA were screened, and the impacts of SLC7A11 on these pathways were validated in vitro. CIA mice were successfully established, revealing significant downregulation of SLC7A11 in RA. Staining results indicated that overexpression of SLC7A11 significantly mitigated joint damage in CIA mice. In vitro experiments demonstrated that overexpression of SLC7A11 inhibited migration, invasion, and Caspase-1 expression levels in TNF-α-induced RA-FLSs. Furthermore, SLC7A11 suppressed inflammation, LDH release, and oxidative stress, while inhibiting pyroptosis. SLC7A11 expression was significantly different in multiple immune cells. The IL-17 pathway was identified as a downstream pathway of SLC7A11, and SLC7A11 inhibited the expression of IL-17 pathway proteins. Additionally, rhIL-17A, an activator of the IL-17 pathway, attenuated the inhibitory effects of SLC7A11 on inflammation, oxidative stress, and pyroptosis. SLC7A11 suppresses pyroptosis to alleviate RA development by inhibiting the IL-17 pathway.

Polo-like kinase 2 ameliorates lipopolysaccharide-induced cardiac injury by blocking cardiomyocyte ferroptosis.

Polo-like kinase 2 (PLK2) is associated with cardiac fibrosis in patients with atrial fibrillation. However, the role of PLK2 in sepsis-induced cardiac injury has not been fully elucidated. We hypothesize that PLK2 may participate in the progression of sepsis-induced cardiac injury. We established a cardiac injury model in C57BL6 mice by injecting lipopolysaccharide (LPS). PLK2 was overexpressed in mice using an adeno-associated virus 9 vector. Cardiac function was evaluated using echocardiography 12 hours after the LPS injection. H9c2 cells were transfected with a PLK2 small interfering RNA. PLK2 was downregulated in the hearts of LPS-treated mice and LPS-stimulated H9c2 cardiomyocytes. Mice in the LPS group presented aggravated cardiac injury and a reduced survival rate with increased cardiac inflammatory responses and oxidative stress. Moreover, PLK2 relieved LPS-induced cardiac injury and increased the survival rate of the mice by weakening the inflammatory response and decreasing oxidative stress. Moreover, the LPS-induced increase in ferroptosis was inhibited by PLK2 overexpression.LPS caused an increase in inflammation and cell injury in H9c2 cardiomyocytes, and PLK2 silencing aggravated LPS-induced cell injury, inflammation, and oxidative stress. Furthermore, PLK2 overexpression increased the expression levels of the antiferroptotic proteins solute carrier family 7 member 11, glutathione peroxidase 4, and ferritin in heart tissue. PLK2 increased the nuclear NRF2 expression level. Moreover, the overexpression of PLK2 increased the phosphorylation of glycogen synthase kinase 3β and promoted the nuclear translocation of NRF2. NRF2 overexpression relieved cardiac injury in mice induced with LPS. However, NRF2 mitigated the deteriorating effects of PLK2 knockdown in the mouse heart. PLK2 ameliorated LPS-induced cardiac injury by blocking cardiomyocyte ferroptosis through NRF2 regulation.

The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications

The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications

DYRK1A-TGF-β signaling axis determines sensitivity to OXPHOS inhibition in hepatocellular carcinoma.

Intervening in mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. Employing kinome-based CRISPR screen, we find that knockout of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) synergizes with OXPHOS inhibitor IACS-010759 in liver cancer cells. Targeting DYRK1A combined with OXPHOS inhibitors activates TGF-β signaling, which is crucial for OXPHOS-inhibition-triggered cell death. Mechanistically, upregulation of glutamine transporter solute carrier family 1 member 5 (SLC1A5) transcription compensates for the increased glutamine requirement upon OXPHOS inhibition. DYRK1A directly phosphorylates SMAD3 Thr132, thereby suppressing the negative impact of TGF-β signaling on transcription of SLC1A5, leading to intrinsic resistance of liver cancer cells to OXPHOS inhibition. Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver cancer models, including xenografts, patient-derived xenografts, and spontaneous tumor model. Our study elucidates how the DYRK1A-TGF-β signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver cancer therapy.

Inhibition of ASIC1a reduces ferroptosis in rheumatoid arthritis articular chondrocytes via the p53/NRF2/SLC7A11 pathway.

The activation of acid-sensing ion channel 1a (ASIC1a) in response to extracellular acidification leads to an increase in extracellular calcium influx, thereby exacerbating the degeneration of articular chondrocytes in rheumatoid arthritis (RA). It has been suggested that the inhibition of extracellular calcium influx could potentially impede chondrocyte ferroptosis. The cystine transporter, solute carrier family 7 member 11 (SLC7A11), is recognized as a key regulator of ferroptosis. Recent studies suggest that the tumor suppressor gene p53 facilitates the induction of ferroptosis by suppressing the upregulation of SLC7A11. This process is mediated by the nuclear factor erythroid 2-related factor 2 (NRF2), a key transcription factor integral to the maintenance of cellular redox homeostasis and the regulation of inflammatory responses. This study aims to investigate the role of ASIC1a in the ferroptosis of RA chondrocytes and to determine the involvement of the p53/NRF2/SLC7A11 pathway in its underlying mechanism. Invitro experiments revealed that acidosis induces ferroptosis and reduces the expression of NRF2 and SLC7A11 in chondrocytes. Moreover, acidification significantly increased p53 protein levels in chondrocytes. Pifithrin-α (PFN-α), a p53 inhibitor, mitigated acidosis-induced ferroptosis and restored the diminished expression of NRF2 and SLC7A11. Furthermore, PcTx-1, an ASIC1a inhibitor, inhibited acidification-induced ferroptosis, enhanced the protein levels of SLC7A11 and NRF2, and reduced p53 expression. Invivo experiments demonstrated that the ASIC1a-specific inhibitor PcTx-1 ameliorated histopathological characteristics of ankle joints in collagen-induced arthritis (CIA) mice, decreased p53 expression, and enhanced NRF2 and SLC7A11 expression in chondrocytes. These findings suggest that ASIC1a inhibition may mitigate acidification-induced ferroptosis in articular chondrocytes in RA, potentially via the p53/NRF2/SLC7A11 pathway.

Unveiling the Role of SLC6A17 in Lung Adenocarcinoma: Prognosis, Pathways, and Therapeutic Implications.

The role of solute carrier family 6 member 17 (SLC6A17) in lung adenocarcinoma (LUAD) is unclear. To address this gap in knowledge, we employed bioinformatics analysis and experimental validation. This research aimed to scrutinize the expression patterns of the SLC6A17 gene across a spectrum of cancers and specifically within LUAD, utilizing data extracted from The Cancer Genome Atlas (TCGA). The correlation between SLC6A17 expression and LUAD prognosis was investigated to assess its diagnostic relevance. The study delved into the possible regulatory mechanisms of SLC6A17, focusing on its links to immune cell infiltration and drug response in LUAD. The examination of SLC6A17 expression was extended to single-cell sequencing data in LUAD, alongside an evaluation of the gene's genomic alterations and clinical implications within this disease context. Validation of SLC6A17 expression levels was conducted using datasets from GSE87340 and various cell lines, employing quantitative real-time polymerase chain reaction (qRTPCR) techniques. SLC6A17 exhibited aberrant expression in both pan-cancer and LUAD. Increased expression of SLC6A17 in LUAD patients was significantly associated with poorer overall survival (p = 0.008), progress-free survival (p = 0.019), and disease specific survival (p = 0.030). In LUAD patients, the levels of SLC6A17 expression were found to be a significant standalone indicator of prognosis, with a p-value of 0.031. SLC6A17 exhibited associations with various pathways, including focal adhesion, ECM receptor interaction, cell cycle, linoleic acid metabolism, pathways in cancer, and more. SLC6A17 expression demonstrated correlations with immune infiltration in LUAD. SLC6A17 expression revealed a notably inverse relationship with several substances, including AR-42, T0901317, tubastatin A, SB52334, and amuvatinib, within the context of LUAD. SLC6A17 was found to be significantly positively regulated in LUAD cell lines. These findings suggest that SLC6A17 indicates the potential of a potential prognostic biomarker and immunotherapeutic target for patients with LUAD.

Differential Expression and Distribution of Slco4a1 and Slco1b2 in an Internal Environment Disorder-induced Hepatocellular Carcinoma Mouse Model.

This study aims to enhance the understanding of underlying mechanisms and potential therapies of the solute carrier organic anion (SLCO) transporter family in internal environment disorder (IED)-induced hepatocellular carcinoma (HCC). This could lead to new therapeutic strategies and offer new directions for the creation of new patents for HCC treatment products. The orthotopic transplantation (OT), IED and IED-based OT (IED-OT) mouse models were established. Expression patterns of Slco4a1 and Slco1b2 were determined using reverse transcriptionquantitative polymerase chain reaction (RT-qPCR), western blotting (WB) and immunohistochemistry (IHC) in various tissues, including lung, stomach, liver, spleen, kidney, colon, small intestine, HCC tissues and adjacent non-cancerous tissues. Animals exhibited symptoms, including weight loss, lethargy, chills, dyspnea, altered hair texture, and gastrointestinal disturbances, confirming the successful establishment of the IED model. The analysis demonstrated differential expression and tissue-specific distribution of Slco4a1 and Slco1b2, which are associated with IED-induced changes. These alterations potentially disrupt organ transport functions, thereby promoting the development of HCC. Additionally, they suggest a role in rebalancing the tumor microenvironment and mitigating damage resulting from abnormal substance accumulation. Changes in SLCO expression and distribution induced by IED may play pivotal roles in the development of HCC. These findings contribute insights that could inform novel therapeutic strategies against HCC.

A Review on the Role of Human Solute Carriers Transporters in Cancer.

The high rate of tumor growth results in an increased need for amino acids. As solute carriers (SLC) transporters are capable of transporting different amino acids, cancer may develop as a result of these transporters' over-expression due to their complex formation with other biological molecules. Therefore, this review investigated the role of SLC transporters in the progression of cancer. We retrieved data from Google Scholar, Web of Science, PubMed, Cochrane Library, and EMBASE regarding the influence of human SLCs on the development of cancer. Articles published in English before August 2024 were included in the study. The overexpression of SLCs is strongly related to tumor cell proliferation and angiogenesis in a number of cancer types including thyroid, pancreatic, lung, hepatocellular, and colon cancers. They are crucial for the stimulation of several biological signaling pathways, particularly mTOR kinase activity, which starts a signaling cascade, protein synthesis, cell growth, and proliferation, and inhibits apoptosis of cancerous cells. Furthermore, they contribute to the activation of PI3K/AKT signaling, which has an impact on the growth, invasion, and death of cancer cells. Thus, SLC transporters become a potential therapeutic target that plays a crucial role in drug resistance, tumor microenvironment regulation, and modulation of immune response. The review recognized the crucial role of SLC transporters in different types of cancer progression. Therefore, to confirm our findings, a case-control study is required to investigate the role of amino acid transporters in cancer development.

Identifying disulfidptosis-related biomarkers in epilepsy based on integrated bioinformatics and experimental analyses.

One of the underlying mechanisms of epilepsy (EP), a brain disease characterized by recurrent seizures, is considered to be cell death. Disulfidptosis, a proposed novel cell death mechanism, is thought to play a part in the pathogenesis of epilepsy, but the exact role is unclear. The gene expression omnibus series (GSE) 33,000 and GSE63808 datasets were used to search for differentially expressed disulfidptosis-related molecules (DE-DRMs). A correlation between the DE-DRMs was discovered. Individuals with epilepsy were then used to investigate molecular clusters based on the expression of DE-DRMs. Following that, the best machine learning model which is validated by GSE143272 dataset and predictor molecules were identified. The correlation between predictive molecules and clinical traits was determined. Based on the in vitro and in vivo seizures models, experimental analyses were applied to verify the DE-DRMs expressions and the correlation between them. Nine molecules were identified as DE-DRMs: glycogen synthase 1 (GYS1), solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), 3-oxoacyl-ACP synthase, mitochondrial (OXSM), leucine rich pentatricopeptide repeat containing (LRPPRC), NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), NUBP iron‑sulfur cluster assembly factor, mitochondrial (NUBPL), and NCK associated protein 1 (NCKAP1). NDUFS1 interacted with NDUFA11, NUBPL, and LRPPRC, while SLC3A2 interacted with SLC7A11. The optimal machine learning model was revealed to be the random forest (RF) model. G protein guanine nucleotide-binding protein alpha subunit q (GNAQ) was linked to sodium valproate resistance. The experimental analyses suggested an upregulated SLC7A11 expression, an increased number of formed SLC3A2 and SLC7A11 complexes, and a decreased number of formed NDUFS1 and NDUFA11 complexes. This study provides previously undocumented evidence of the relationship between disulfidptosis and EP. In addition to suggesting that SLC7A11 may be a specific DRM for EP, this research demonstrates the alterations in two disulfidptosis-related protein complexes: SLC7A11-SLC3A2 and NDUFS1-NDUFA11.

JAG1/Notch Pathway Inhibition Induces Ferroptosis and Promotes Cataractogenesis.

Cataracts remain the leading cause of visual impairment worldwide, yet the underlying molecular mechanisms, particularly in age-related cataracts (ARCs), are not fully understood. The Notch signaling pathway, known for its critical role in various degenerative diseases, may also contribute to ARC pathogenesis, although its specific involvement is unclear. This study investigates the role of Notch signaling in regulating ferroptosis in lens epithelial cells (LECs) and its impact on ARC progression. RNA sequencing of anterior lens capsule samples from ARC patients revealed a significant downregulation of Notch signaling, coupled with an upregulation of ferroptosis-related genes. Notch1 expression decreased, while ferroptosis markers increased in an age-dependent manner. In vitro, upregulation of Notch signaling alleviated ferroptosis by decreasing ferritin heavy chain 1 (FTH1) and p53 levels while enhancing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). Conversely, inhibition of Notch signaling exacerbated ferroptosis, as evidenced by reduced Nrf2, GPX4, and SLC7A11 expression. These findings suggest that downregulation of Notch signaling promotes ferroptosis in LECs by impairing the Nrf2/GPX4 antioxidant pathway, thereby contributing to ARC development. This study offers new insights into ARC pathogenesis and highlights the Notch signaling pathway as a potential therapeutic target for preventing or mitigating ARC progression.

Structural and Dynamic Assessment of Disease‐Causing Mutations for the Carnitine Transporter OCTN2

AbstractPrimary carnitine deficiency (PCD) is a rare autosomal recessive genetic disorder caused by missense mutations in the SLC22A5 gene encoding the organic carnitine transporter novel type 2 (OCTN2). This study investigates the structural consequences of PCD‐causing mutations, focusing on the N32S variant. Using an alpha‐fold model, molecular dynamics simulations reveal altered interactions and dynamics suggesting potential mechanistic changes in carnitine transport. In addition, we identify mutation hotspots (R169, E452) across the SLC family with the major facilitator superfamily (MFS) fold. Our data demonstrates the applicability of structural modeling for linking genetic information and clinical observations and providing a rationale for the influence of disease‐causing mutations on protein dynamics.

SLC35C2 promotes stemness and progression in hepatocellular carcinoma by activating lipogenesis.

Metabolic reprogramming plays a critical role in tumorigenesis and progression, including hepatocellular carcinoma (HCC). The Solute Carriers (SLCs) family is responsible for the transport of a range of nutrients and has been linked to various cancers. Cancer stem cells (CSC) are a contributing factor to the recurrence and metastasis of HCC. However, the regulatory genes that govern this process remain unclear. The present study identified SLC35C2 as a crucial factor in maintaining the stem-cell characteristics of HCC cells through CRISPR-dCas9 screening. Further investigation demonstrated that SLC35C2 was significantly elevated in HCC tissues and correlated with a poor prognosis in HCC patients. It is an independent prognostic factor for HCC patients. The knockdown and overexpression of SLC35C2 inhibited or promoted stemness in HCC cell. Both in vitro and in vivo studies demonstrated that SLC35C2 promoted the proliferation, migration, invasion and metastasis in HCC cells. Through RNA-seq and lipidomics analysis, it was found that SLC35C2 regulated lipid reprogramming, particularly triglyceride synthesis. Mechanistically, SLC35C2 stimulated lipogenesis through the up-regulation of SREBP1, ACC, FAS, and SCD-1, thereby increasing lipid accumulation in HCC cells. SLC35C2 interacted with ACSL4, which plays a critical role in lipogenesis, and to protect it from degradation. Inhibition of ACSL4 with PRGL493 can reverse the lipogenesis, stemness and proliferation induced by SLC35C2 overexpression. In conclusion, our study demonstrates the pivotal role of SLC35C2 in stemness and malignant progression in HCC by promoting lipogenesis. These findings suggest that SLC35C2 is a prognostic marker and promising therapeutic target for HCC treatment.

Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylation-mediated stabilization of PD-L1.

Itaconate is a metabolite catalyzed by cis-aconitate decarboxylase (ACOD1), which is mainly produced by activated macrophages and secreted into the extracellular environment to exert complex bioactivity. In the tumor microenvironment, itaconate is concentrated and induces an immunosuppressive response. However, whether itaconate can be taken up by tumor cells and its mechanism of action remain largely unclear. Here, we identified solute carrier family 13 member 3 (SLC13A3) as a key protein transporting extracellular itaconate into cells, where it elevates programmed cell death ligand 1 (PD-L1) protein levels and decreases the expression of immunostimulatory molecules, thereby promoting tumor immune evasion. Mechanistically, itaconate alkylates the cysteine 272 residue on PD-L1, antagonizing PD-L1 ubiquitination and degradation. Consequently, SLC13A3 inhibition enhances the efficacy of anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) immunotherapy and improves the overall survival rate in syngeneic mouse tumor models. Collectively, our findings identified SLC13A3 as a key transporter of itaconate and revealed its immunomodulatory role, providing combinatorial strategies to overcome immunotherapy resistance in tumors.

SLC27A3 downregulation restores Th17/Treg balance and alleviates COPD via JAK2/STAT3 pathway inhibition.

The main goal of this investigation is to find out how solute carrier family 27 member 3 (SLC27A3) is expressed in the lung tissue of mice with chronic obstructive pulmonary disease (COPD), and how it relates to lung function. A model of COPD was established by exposing organisms to cigarette smoke, followed by investigating the role of SLC27A3 in COPD through experiments conducted both in living organisms and in laboratory settings. Knockout mice lacking SLC27A3 were produced through siRNA transfection to investigate lung function and inflammatory response, using methods such as hematoxylin-eosin staining and enzyme-linked immunosorbent assay. Western blotting was carried out to analyze the expression of SLC27A3. Naïve CD4+ T-cells were stimulated with anti-CD3, anti-CD28, transforming growth factor (TGF)-β, and/or interleukin (IL)-6, and their differentiation into Th17 or Treg cells was promoted, as assessed by flow cytometry. The pathway expression of JAK2/STAT3 was detected using Western blotting. Mice with COPD that had higher expression levels of SLC27A3 in their lung tissue display abnormalities in lung architecture and function, as well as an imbalance between Th17 and Tregs and an elevated inflammatory response. In COPD mice with SLC27A3 knockdown, the JAK2/STAT3 pathway was repressed, lung inflammation was decreased, Th17/Treg balance was improved, and lung functioning was improved. In conclusion, the findings of this study suggest that downregulating SLC27A3 has the potential to attenuate the inflammatory response, mitigate COPD progression, and rebalance the Th17/Treg ratio by inhibiting the JAK2/STAT3 signaling pathway. These results lay a foundation for utilizing SLC27A3 as a potential therapeutic target to modulate the JAK2/STAT3 pathway for the treatment of COPD, with the aim of enhancing lung function, reducing inflammation, and restoring Th17/Treg equilibrium in a clinical context.

SLC39A14 promotes the development of esophageal squamous cell carcinoma through PI3K/Akt/mTOR signaling pathway.

This study aims to investigate the expression of solute carrier family 39 member 14 (SLC39A14) in esophageal squamous cell carcinoma (ESCC) tissues and its prognosis, as well as the impact of SLC39A14 expression on the biological behavior of ESCC cells and associated mechanisms. Bioinformatics analysis was utilized to compare the differential expression of SLC39A14 mRNA between esophageal cancer tissues and adjacent non-cancerous tissues. Immunohistochemistry was employed to evaluate SLC39A14 protein expression in human ESCC tissues and normal esophageal tissues, followed by an analysis of its association with clinicopathological parameters in esophageal cancer patients. Through cell proliferation, migration, invasion, and Western blot assays, we deeply evaluated the specific effects of SLC39A14 gene knockdown (or overexpression) on ESCC cells and explored its potential biological functions in ESCC. Subsequently, we validated the role of SLC39A14 in ESCC in a xenograft model. Furthermore, LY294002 drug intervention was used to verify the regulatory effect of SLC39A14 on PI3K/Akt/mTOR signaling pathway. Both mRNA and protein levels of SLC39A14 were significantly elevated in tumor tissues from ESCC patients compared to adjacent normal tissues. Notably, higher levels of SLC39A14 expression positively correlated with ESCC tumor size (p=0.010) and clinical T stage (p=0.025), while exhibiting a negative correlation with overall patient survival rates (p=0.023). In vitro experiments demonstrated that knocking down SLC39A14 significantly inhibited cell proliferation, migration and invasion. In vivo study showed that SLC39A14 facilitated progression within murine models bearing ESCC tumors. Mechanistic analyses suggested that pro-carcinogenic effects exerted by SLC39A14 are mediated through activation of the PI3K/Akt/mTOR signaling pathway. Our findings suggest that SLC39A14 may serve as a potential biomarker for ESCC due to its pro-oncogenic role during ESCC progression.