Beyond the Microscope: A Technological Overture for Cervical Cancer Detection.

Cervical cancer is a common and preventable disease that poses a significant threat to women's health and well-being. It is the fourth most prevalent cancer among women worldwide, with approximately 604,000 new cases and 342,000 deaths in 2020, according to the World Health Organization. Early detection and diagnosis of cervical cancer are crucial for reducing mortality and morbidity rates. The Papanicolaou smear test is a widely used screening method that involves the examination of cervical cells under a microscope to identify any abnormalities. However, this method is time-consuming, labor-intensive, subjective, and prone to human errors. Artificial intelligence techniques have emerged as a promising alternative to improve the accuracy and efficiency of Papanicolaou smear diagnosis. Artificial intelligence techniques can automatically analyze Papanicolaou smear images and classify them into normal or abnormal categories, as well as detect the severity and type of lesions. This paper provides a comprehensive review of the recent advances in artificial intelligence diagnostics of the Papanicolaou smear, focusing on the methods, datasets, performance metrics, and challenges. The paper also discusses the potential applications and future directions of artificial intelligence diagnostics of the Papanicolaou smear.

Exploration of Potential Breath Biomarkers of Chronic Kidney Disease through Thermal Desorption-Gas Chromatography/Mass Spectrometry.

Breath volatile organic compound (VOC) analysis is a non-invasive tool for assessing health status; the compositional profile of these compounds in the breath of patients with chronic kidney disease is believed to change with decreasing renal function. We aimed to identify breath VOCs for recognizing patients with chronic kidney disease. Using thermal desorption-gas chromatography/mass spectrometry, untargeted analysis of breath markers was performed using breath samples of healthy controls (n = 18) versus non-dialysis (n = 21) and hemodialysis (n = 12) patients with chronic kidney disease in this cross-sectional study. A total of 303 VOCs alongside 12 clinical variables were used to determine the breath VOC profile. Metabolomic analysis revealed that age, systolic blood pressure, and fifty-eight breath VOCs differed significantly between the chronic kidney disease group (non-dialysis + hemodialysis) and healthy controls. Thirty-six VOCs and two clinical variables that showed significant associations with chronic kidney disease in the univariate analysis were further analyzed. Different spectra of breath volatile organic compounds between the control and chronic kidney disease groups were obtained. A multivariate model incorporating age, 2-methyl-pentane, and cyclohexanone showed high performance (accuracy, 86%) in identifying patients with chronic kidney disease with odds ratios of 0.18 (95% CI, 0.07-2.49, p = 0.013); 2.10 (0.94-2.24, p = 0.025); and 2.31 (0.88-2.64, p = 0.008), respectively. Hence, this study showed that renal dysfunction induces a characteristic profile of breath VOCs that can be used as non-invasive potential biomarkers in screening tests for CKD.

CervixFormer: A Multi-scale swin transformer-Based cervical pap-Smear WSI classification framework.

BACKGROUND AND OBJECTIVES: Cervical cancer affects around 0.5 million women per year, resulting in over 0.3 million fatalities. Therefore, repetitive screening for cervical cancer is of utmost importance. Computer-assisted diagnosis is key for scaling up cervical cancer screening. Current recognition algorithms, however, perform poorly on the whole-slide image (WSI) analysis, fail to generalize for different staining methods and on uneven distribution for subtype imaging, and provide sub-optimal clinical-level interpretations. Herein, we developed CervixFormer-an end-to-end, multi-scale swin transformer-based adversarial ensemble learning framework to assess pre-cancerous and cancer-specific cervical malignant lesions on WSIs. METHODS: The proposed framework consists of (1) a self-attention generative adversarial network (SAGAN) for generating synthetic images during patch-level training to address the class imbalanced problems; (2) a multi-scale transformer-based ensemble learning method for cell identification at various stages, including atypical squamous cells (ASC) and atypical squamous cells of undetermined significance (ASCUS), which have not been demonstrated in previous studies; and (3) a fusion model for concatenating ensemble-based results and producing final outcomes. RESULTS: In the evaluation, the proposed method is first evaluated on a private dataset of 717 annotated samples from six classes, obtaining a high recall and precision of 0.940 and 0.934, respectively, in roughly 1.2 minutes. To further examine the generalizability of CervixFormer, we evaluated it on four independent, publicly available datasets, namely, the CRIC cervix, Mendeley LBC, SIPaKMeD Pap Smear, and Cervix93 Extended Depth of Field image datasets. CervixFormer obtained a fairly better performance on two-, three-, four-, and six-class classification of smear- and cell-level datasets. For clinical interpretation, we used GradCAM to visualize a coarse localization map, highlighting important regions in the WSI. Notably, CervixFormer extracts feature mostly from the cell nucleus and partially from the cytoplasm. CONCLUSIONS: In comparison with the existing state-of-the-art benchmark methods, the CervixFormer outperforms them in terms of recall, accuracy, and computing time.

Primary Malignant Melanoma of the Breast Presenting as a Breast Abscess: A Case Report.

Primary malignant melanoma in breast parenchyma (PMB) is an extremely rare disease, and the most common presentation is a palpable breast lump. To the best of our knowledge, a case of PMB presenting as a breast abscess has not been reported in English literatures. We present a case of PMB that manifested as a recurrent breast abscess in a 71-year-old woman. On MRI, an enhancing solid mass with a cystic or necrotic portion was revealed with some high signal intensities on precontrast-enhanced T1-weighted images and a dark rim on T2-weighed images. The MRI features played a pivotal role in identifying the underlying malignant condition and making an accurate diagnosis of this rare case of PMB with unusual clinical presentation.

POEMS Syndrome: Presented as Idiopathic Multicentric Castleman Disease of Plasma Cell Variant for Eight Years and Dramatic Treatment with Siltuximab Followed by Autologous Peripheral Blood Stem Cell Transplantation.

BACKGROUND: POEMS syndrome (POEMS) is a rare plasma cell clonal paraneoplastic syndrome consisting of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes presenting with idiopathic multicentric Castleman disease (iMCD) histology, the treatment of which has not yet been well established. iMCD is also a distinctive rare non-clonal lymphoproliferative disorder, of which dramatic response to Siltuximab, a monoclonal anti-IL-6 antibody, has been reported recently. METHODS: the differential diagnosis between POEMS and iMCD can be very challenging because of the identical histology, overlapping similar symptoms such as polyneuropathy, and vital signs insidiously presented to diagnose POEMS. RESULTS: here, we report the case of a 53-year-old man with iMCD treated for 8 years developing sequential polyneuropathy, monoclonal gammopathy, and bone lytic lesions, all of which were confirmed after his iMCD achieved complete remission resulting from siltuximab administration and finally confirmed as POEMS. CONCLUSIONS: we describe the clinical ambiguity of disease presenting that we can face in the real world between iMCD and POEMS and emphasise careful, enduring observation lasting several years.

SK1 Inhibitor RB005 Induces Apoptosis in Colorectal Cancer Cells through SK1 Inhibition Dependent and Independent Pathway.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is the fourth leading cause of cancer- related death globally, with a high incidence rate in economically fast-growing countries. Sphingosine- 1-phosphate (S1P) is a bioactive lipid mediator that plays critical roles in cancer cell proliferation, migration, and angiogenesis converted by the isoforms of sphingosine kinase (SK1 and SK2). SK1 is highly expressed in colorectal cancer; its inhibitors suppress the formation of S1P and increase ceramide levels having a pro-apoptotic function. RB005 is a selective SK1 inhibitor and a structural analog of PP2A activator FTY720. The purpose of this study is to test whether RB005, an SK1 inhibitor, can be used as an anticancer agent by inhibiting the growth of colon cancer cells. METHODS: We performed MTT and colony-forming assay using colon cancer cell lines HT29 and HCT116 cells to examine the cell toxicity effect of RB005. To determine whether apoptosis of RB005 in colon cancer cell line is due to SK1 inhibition or other mechanisms due to its structural similarity with FTY720, we conducted LC/MS, siRNA knockdown, and PP2A activity experiments. RESULTS: RB005 notably inhibited CRC cell growth and proliferation compared to PF543 and ABC294640 by inducing the mitochondria-mediated intrinsic apoptotic pathway. Apoptotic cell death is caused by increased mitochondrial permeability Initiated by the activation of pro-apoptotic protein BAX, increased ceramides, and activation of PP2A. Also, RB005 treatment in HT29 cells did not change the expression level of SK1, but strikingly decreased SK1 activity and S1P levels. All these events of cell death and apoptosis were less effective when SK1 was knocked down by siRNA. CONCLUSION: This result indicates that RB005 shows the in-vitro anti-CRC effect by inhibiting SK1 activity and PP2A activation, increasing proapoptotic ceramide levels following the activation of the intrinsic apoptotic pathway.

A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation.

Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P is linked to a pathological outcome with inflammation, cancer metastasis, or angiogenesis, etc. In this regard, SPHK/S1P axis regulation has been a specific issue in the anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhancing serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs, which eventually induced an unusual environment with a high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase), which contributes a partial increase in Cers. Collectively, a dansyl-modified DPF-543 relatively enhanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.

Incidental Detection of Ovarian Cancer as a Solitary Peridiaphragmatic Distant Lymph Node Metastasis without Pelvic Lesions on 18F-FDG PET/CT.

The spreading pattern of ovarian carcinoma is unique and unlike most other cancers, because exfoliated ovarian cancer cells primarily disseminate within the abdominal cavity, which are then transported throughout the peritoneum by physiological peritoneal fluid. An initial manifestation of a solitary peridiaphragmatic distant metastatic lymph node without peritoneal involvement is very rare. This study reports a case with an incidentally found single hypermetabolic mass in the peridiaphragmatic space without a pelvic lesion in the baseline staging 18 F-FDG PET/CT that histologically turned out to be metastatic serous papillary carcinoma due to ovarian cancer. 18F-FDG PET/CT may allow the identification of the initial manifestation of unexpected distant oligometastatic statuses of an unknown primary ovarian cancer.

A Bioassay Using a Pentadecanal Derivative to Measure S1P Lyase Activity.

Sphingosine-1-phosphate (S1P) is a unique lipid ligand binding to S1P receptors to transduce various cell survival or proliferation signals via small G proteins. S1P lyase (S1PL) is the specific enzyme that degrades S1P to phosphoethanolamine and (2E)-hexadecenal and therefore regulates S1P levels. S1PL also degrades dihydrosphingosine-1-phosphate (Sa1P), with a higher affinity to produce hexadecanal. Here, we developed a newly designed assay using a C17-Sa1P substrate that degrades into pentadecanal and phosphoethanolamine. For higher sensitivity in pentadecanal analysis, we developed a quantitative protocol as well as a 5,5-dimethyl cyclohexanedione (5,5-dimethyl CHD) derivatization method. The derivatization conditions were optimized for the reaction time, temperature, and concentrations of the 5,5-dimethyl CHD reagent, acetic acid, and ammonium acetate. The S1PL reaction in the cell lysate after spiking 20 µM of C17-Sa1P for 20 min was linear to the total protein concentrations of 50 µg. The S1PL levels (4 pmol/mg/min) were readily detected in this HPLC with fluorescence detection (λex = 366 nm, λem = 455 nm). The S1PL-catalyzed reaction was linear over 30 min and yielded a Km value of 2.68 µM for C17-Sa1P. This new method was validated to measure the S1PL activity of mouse embryonal carcinoma cell lines of the standard cell (F9-0), S1PL knockdown cells (F9-2), and S1PL-overexpressed cells (F9-4). Furthermore, we treated F9-4 cells with different S1PL inhibitors such as FTY720, 4-deoxypyridoxine (DOP), and the deletion of pyridoxal-5-phosphate (P5P), an essential cofactor for S1PL activity, and observed a significant decrease in pentadecanal relative to the untreated cells. In conclusion, we developed a highly sensitive S1PL assay using a C17-Sa1P substrate for pentadecanal quantification for application in the characterization of S1PL activity in vitro.

Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Molecular subtypes of triple-negative breast cancer: understanding of subtype categories and clinical implication.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous entity that encompasses several subtypes with distinct molecular characteristics. The patients with TNBCs show unpredictable response to the chemotherapy, and further there is the lack of effective agents. Thus, many studies have been underway to discover targeted therapy suitable for patients with specific genetic alterations in each molecular subtypes. TNBCs are classified as four major molecular subtypes according to the gene expression patterns. These are luminal androgen receptor (LAR), mesenchymal-like, immunomodulatory (IM), and basal-like types. CONCLUSION: Here, we discuss the unique molecular features of each subtype as well as promising targets for anti-cancer therapy.

Predicting Carcinogenic Mechanisms of Non-Genotoxic Carcinogens via Combined Analysis of Global DNA Methylation and In Vitro Cell Transformation.

An in vitro cell transformation assay (CTA) is useful for the detection of non-genotoxic carcinogens (NGTXCs); however, it does not provide information on their modes of action. In this study, to pursue a mechanism-based approach in the risk assessment of NGTXCs, we aimed to develop an integrated strategy comprising an in vitro Bhas 42 CTA and global DNA methylation analysis. For this purpose, 10 NGTXCs, which were also predicted to be negative through Derek/Sarah structure-activity relationship analysis, were first tested for transforming activity in Bhas 42 cells. Methylation profiles using reduced representation bisulfite sequencing were generated for seven NGTXCs that were positive in CTAs. In general, the differentially methylated regions (DMRs) within promoter regions showed slightly more bias toward hypermethylation than the DMRs across the whole genome. We also identified 13 genes associated with overlapping DMRs within the promoter regions in four NGTXCs, of which seven were hypermethylated and six were hypomethylated. Using ingenuity pathway analysis, the genes with DMRs at the CpG sites were found to be enriched in cancer-related categories, including "cell-to-cell signaling and interaction" as well as "cell death and survival". Moreover, the networks related to "cell death and survival", which were considered to be associated with carcinogenesis, were identified in six NGTXCs. These results suggest that epigenetic changes supporting cell transformation processes occur during non-genotoxic carcinogenesis. Taken together, our combined system can become an attractive component for an integrated approach for the testing and assessment of NGTXCs.

Reliable screening and classification of phosphodiesterase type 5 inhibitors in dietary supplements using gas chromatography / mass spectrometry combined with specific common ions.

Illegal dietary supplements adulterated with phosphodiesterase type 5 inhibitors (PDE-5i) are increasingly widely distributed through internet markets and underground routes. For this reason, it demands development of reliable screening methods to determine a wide range of PDE-5i drugs in various types of dietary supplements. Herein, we developed a screening method using gas chromatography-mass spectrometry (GC-MS) for simultaneous detection of 53 PDE-5i drugs in supplements. Common formulations (such as capsule, powder, pill, and tablet) of supplements with complicated matrices were treated by simple liquid-liquid extraction and trimethylsilyl (TMS) derivatization. With the aid of TMS derivatization, 53 PDE-5i drugs could be successfully separated and detected within 15 min, using a short microbore GC column (15 m). Moreover, owing to enhanced detection sensitivity and selectivity of PDE-5i TMS derivatives, 0.5 mg of sample was sufficient to screen and confirm targeted PDE-5i drugs. In this study, specific common ions according to structural characteristics of PDE-5i drugs were found under the electron ionization (EI) of their TMS derivatives. These specific common fragments could reflect the common pharmacophores for 4 classes of PDE-5i drugs (sildenafil, other sildenafil, vardenafil, and tadalafil analogues). Based on characteristic EI fragment ions, extracted common ion chromatograms (ECICs) and discriminant analysis (DA) were effectively used for reliable screening and classification of various types of PDE-5i drugs. Specific ECICs and DA using characteristic EI fragments here will aid in identification of newly emerging PDE-5i counterfeits in supplements. This study will be helpful to supervise illegal adulteration of PDE-5i drugs in dietary supplements to protect public health and consumer safety.

Differential expressions of L1-chimeric transcripts in normal and matched-cancer tissues.

L1s are a cis-regulatory elements and contain bidirectional internal promoters within the 5' untranslated region (UTR). L1s provide bidirectional promoters that generate alternative transcripts and affect differential expressions in the human genome. In particular, L1 antisense promoters (L1ASPs) could produce aberrant transcripts in cancer tissues compared to normal tissues. In this study, we identified the L1-chimeric transcripts derived from L1ASPs and analyzed relative expression of L1-chimeric transcripts between normal and matched-cancer tissues. First, we collected 425 L1-chimeric transcripts by referring to previous studies. Through the manual inspection, we identified 144 L1-chimeric transcripts derived from 44 L1 antisense promoters, suggesting that the antisense promoter acted as an alternative promoter. We analyzed relative gene expression levels of 16 L1-chimeric transcripts between matched cancer-normal tissue pair (lung, liver, gastric, kidney, thyroid, breast, ovary, uterus, and prostate) using real-time quantitative PCR (RT-qPCR) and investigated putative transcription factor binding motifs to determine activity of L1ASPs. Taken together, we propose that L1ASPs could contribute to the differential gene expression between normal and cancer tissues.

Subepithelial Spread of Early Gastric Signet Ring Cell Carcinoma: How Far They Can Reach?

INTRODUCTION: Although signet ring cell carcinoma (SRC) is a poorly differentiated cancer subtype, recent studies suggest that endoscopic resection can be applied in small, mucosal early gastric SRC. However, other studies report frequent positive lines at the lateral resection margin after endoscopic treatment. Subepithelial spread beneath normal mucosa can exist in SRC, and such lesions may be the cause of positive margins after endoscopic resection. Thus, we conducted a retrospective study in order to evaluate the significance of subepithelial spread in early gastric SRC. METHOD: Medical records of early gastric SRC patients who underwent surgery or endoscopic resection from January 2011 to December 2016 at a single tertiary hospital (Daejeon, South Korea) were reviewed to examine subepithelial spread and clinical datum. Two expert pathologists reviewed all pathologic specimens, and only patients showing a pure SRC component were included. RESULTS: Eighty-six patients were initially enrolled, and subepithelial spread existed in 62 patients (72.1%). The mean distance of subepithelial spread was 1,132.1 µm, and the maximal distance was 6,000 µm. Only discoloration was significantly associated with the presence of a subepithelial spread (p < 0.05, χ2 test, and logistic regression test). Distance of subepithelial spread did not correlate with total lesion size. CONCLUSION: Subepithelial spread of early gastric SRC occurs frequently and can reach up to 6 mm. Lesion discoloration may be associated with the presence of subepithelial spread. Our results suggest that careful decision of the margin is needed when performing endoscopic resection of early gastric SRC.

Sesquiterpene Alcohol Cedrol Chemosensitizes Human Cancer Cells and Suppresses Cell Proliferation by Destabilizing Plasma Membrane Lipid Rafts.

Chemosensitization of cancer cells with small molecules may improve the therapeutic index of antitumoral agents by making tumor cells sensitive to the drug regimen and thus overcome the treatment resistance and side effects of single therapy. Cell membrane lipid rafts are known to transduce various signaling events in cell proliferation. Sensitizing cancer cells may cause modulation of membrane lipid rafts which may potentially be used in improving anticancer drug response. Cedrol, a natural sesquiterpene alcohol, was used to treat human leukemia K562 and colon cancer HT-29 cell lines, and effects were observed. Cedrol decreased the cell viability by inducing apoptosis in both cell lines by activation of pro-apoptosis protein BID and inhibition of anti-apoptosis proteins Bcl-X L , Bcl-2, and XIAP. Cedrol activated the caspase-9-dependent mitochondrial intrinsic pathway of apoptosis. Furthermore, cedrol inhibited the levels of pAKT, pERK, and pmTOR proteins as well as nuclear and cytoplasmic levels of the p65 subunit of NF-κB. Cedrol caused redistribution of cholesterol and sphingomyelin contents from membrane lipid raft, which was confirmed by a combined additive effect with methyl-ß-cyclodextrin (lipid raft-disrupting agent). Lipid raft destabilization by cedrol led to the increased production of ceramides and inhibition of membrane-bound NADPH oxidase 2 enzyme activity. Cholesterol/sphingomyelin-redistributing abilities of cedrol appear as a novel mechanism of growth inhibition of cancer cells. Cedrol can be classified as a natural lipid raft-disrupting agent with possibilities to be used in general studies involving membrane lipid raft modifications.

The nature of triple-negative breast cancer classification and antitumoral strategies.

Identifying the patterns of gene expression in breast cancers is essential to understanding their pathophysiology and developing anticancer drugs. Breast cancer is a heterogeneous disease with different subtypes determined by distinct biological features. Luminal breast cancer is characterized by a relatively high expression of estrogen receptor (ER) and progesterone receptor (PR) genes, which are expressed in breast luminal cells. In ~25% of invasive breast cancers, human epidermal growth factor receptor 2 (HER2) is overexpressed; these cancers are categorized as the HER2 type. Triple-negative breast cancer (TNBC), in which the cancer cells do not express ER/PR or HER2, shows highly aggressive clinical outcomes. TNBC can be further classified into specific subtypes according to genomic mutations and cancer immunogenicity. Herein, we discuss the brief history of TNBC classification and its implications for promising treatments.

Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases.

The endoplasmic reticulum (ER) is not only important for protein synthesis and folding but is also crucial for lipid synthesis and metabolism. In the current study, we demonstrate an important role of ceramide synthases (CerS) in ER stress and NAFLD progression. Ceramide is important in sphingolipid metabolism, and its acyl chain length is determined by a family of six CerS in mammals. CerS2 generates C22-C24 ceramides, and CerS5 or CerS6 produces C16 ceramide. To gain insight into the role of CerS in NAFLD, we used a high-fat diet (HFD)-induced NAFLD mouse model. Decreased levels of CerS2 and increased levels of CerS6 were observed in the steatotic livers of mice fed a HFD. In vitro experiments with Hep3B cells indicated the protective role of CerS2 and the detrimental role of CerS6 in the ER stress response induced by palmitate treatment. In particular, CerS6 overexpression increased sterol regulatory element-binding protein-1 (SREBP-1) cleavage with decreased levels of INSIG-1, leading to increased lipogenesis. Blocking ER stress abrogated the detrimental effects of CerS6 on palmitate-induced SREBP-1 cleavage. In accordance with the protective role of CerS2 in the palmitate-induced ER stress response, CerS2 knockdown enhanced ER stress and SREBP-1 cleavage, and CerS2 heterozygote livers exhibited a stronger ER stress response and higher triglyceride levels following HFD. Finally, treatment with a low dose of bortezomib increased hepatic CerS2 expression and protected the development of NAFLD following HFD. These results indicate that CerS and its derivatives impact hepatic ER stress and lipogenesis differently and might be therapeutic targets for NAFLD.