{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:05:12Z","timestamp":1781071512323,"version":"3.54.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether early on-treatment expression of ectonucleotide pyrophosphatase\/phosphodiesterase 1 (ENPP1) and interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) in peripheral blood mononuclear cells (PBMCs) could serve as biomarkers for predicting hepatitis B surface antigen (HBsAg) clearance and therapeutic responses to pegylated interferon-\u03b1 (Peg-IFN-\u03b1) in HBeAg-negative chronic hepatitis B (CHB) patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective study, HBeAg-negative CHB patients received Peg-IFN-\u03b1 therapy for 48 weeks. Patients were categorized into virological response (VR) or non-virological response (NVR) groups based on changes in HBV DNA and HBsAg levels at week 48, and further stratified into serological response (SR) or non-serological response (NSR) groups based on the occurrence of HBsAg loss or seroconversion. ENPP1 and IFIT2 mRNA levels in PBMCs were quantified using real-time quantitative PCR. Correlations between gene expression and HBsAg reduction were evaluated using Spearman\u2019s rank correlation analysis. Factors independently associated with VR and SR were identified using univariate and multivariate logistic regression analyses. The discriminative ability of individual biomarkers and combined predictive models was assessed by receiver operating characteristic (ROC) curve analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both ENPP1 and IFIT2 mRNA levels were significantly elevated in the VR and SR groups during early treatment. Expression levels of both genes at weeks 12 and 24 positively correlated with the magnitude of HBsAg reduction, and their early induction at week 12 was associated with subsequent HBsAg decline. Multivariate analyses identified ENPP1 and IFIT2 mRNA levels at weeks 12 and 24 as independent predictors of VR and SR. ENPP1 expression at week 12 demonstrated the highest predictive accuracy for VR (AUC\u00a0=\u00a00.7645), while ENPP1 at week 24 showed moderate predictive value for SR (AUC\u00a0=\u00a00.7399). In contrast, IFIT2 consistently exhibited superior predictive performance for VR (AUC\u00a0=\u00a00.8791) and for SR at week 24 (AUC\u00a0=\u00a00.8879). The combination of ENPP1 and IFIT2 further improved predictive accuracy for both VR (AUC\u00a0=\u00a00.9098) and SR (AUC\u00a0=\u00a00.9217).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ENPP1 and IFIT2 in PBMCs represent valuable biomarkers for early prediction of Peg-IFN-\u03b1 treatment efficacy and HBsAg clearance in HBeAg-negative CHB patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1796228","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T05:39:51Z","timestamp":1781069991000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ENPP1 and IFIT2 in PBMCs as early predictive biomarkers for HBsAg clearance and responses to Peg-IFN-\u03b1 in HBeAg-negative chronic hepatitis B patients"],"prefix":"10.3389","volume":"17","author":[{"given":"Hao","family":"Pang","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglin","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Central Laboratory, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00760-9","article-title":"Global burden of hepatitis B virus: current status, missed opportunities and a call for action","volume":"20","author":"Hsu","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"618","DOI":"10.3390\/v16040618","article-title":"Burden, outcome, and comorbidities of extrahepatic manifestations in hepatitis B virus infections","volume":"16","author":"Songtanin","year":"2024","journal-title":"Viruses"},{"key":"B3","unstructured":"Hepatitis B\n          \n          2023"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.1997.tb00503.x","article-title":"Natural history of chronic hepatitis B virus infection: an immunopathological study","volume":"12","author":"Chu","year":"1997","journal-title":"J Gastroenterol Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13246","article-title":"A combination of different diagnostic tools allows identification of inactive hepatitis B virus carriers at a single time point evaluation","volume":"37","author":"Maimone","year":"2017","journal-title":"Liver Int"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28552","article-title":"Serum levels of hepatitis B surface antigen and DNA can predict inactive carriers with low risk of disease progression","volume":"64","author":"Liu","year":"2016","journal-title":"Hepatology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.14218\/jcth.2023.00320","article-title":"Guidelines for the prevention and treatment of chronic hepatitis B (version 2022)","volume":"11","author":"You","year":"2023","journal-title":"J Clin Transl Hepatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/cld.728","article-title":"Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance","volume":"67","author":"Terrault","year":"2018","journal-title":"Hepatology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21612","article-title":"HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up","volume":"45","author":"Chu","year":"2007","journal-title":"Hepatology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.01.042","article-title":"Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death","volume":"138","author":"Chen","year":"2010","journal-title":"Gastroenterology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.11.039","article-title":"Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside\/nucleotide analogue therapy: finite treatment duration unlikely","volume":"58","author":"Chevaliez","year":"2013","journal-title":"J Hepatol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1016\/j.cgh.2021.08.037","article-title":"Severe acute exacerbation after cessation of nucleos(t)ide analog for chronic hepatitis B: a real-world study of routine practice","volume":"20","author":"Hsu","year":"2022","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1177\/2049936120965027","article-title":"Advances in hepatitis B therapeutics","volume":"7","author":"Soriano","year":"2020","journal-title":"Ther Adv Infect Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.05.044","article-title":"Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial)","volume":"61","author":"Ning","year":"2014","journal-title":"J Hepatol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa040431","article-title":"Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B","volume":"351","author":"Marcellin","year":"2004","journal-title":"N Engl J Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"306.e7","DOI":"10.1016\/j.cmi.2017.07.016","article-title":"Predictive role of serum HBsAg and HBcrAg kinetics in patients with HBeAg-negative chronic hepatitis B receiving pegylated interferon-based therapy","volume":"24","author":"Chuaypen","year":"2018","journal-title":"Clin Microbiol Infect"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.894410","article-title":"Quantitative anti-HBc combined with quantitative HBsAg can predict HBsAg clearance in sequential combination therapy with PEG-IFN-\u03b1 in NA-suppressed chronic hepatitis B patients","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nri2314","article-title":"Interferon-inducible antiviral effectors","volume":"8","author":"Sadler","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.26.15623","article-title":"Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays","volume":"95","author":"Der","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B20","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.virol.2022.12.014","article-title":"The antiviral activity of tripartite motif protein 38 in hepatitis B virus replication and gene expression and its association with treatment responses during PEG-IFN-\u03b1 antiviral therapy","volume":"579","author":"Luo","year":"2023","journal-title":"Virology"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2016.67","article-title":"Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication","volume":"15","author":"Tan","year":"2018","journal-title":"Cell Mol Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.12.009","article-title":"Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication","volume":"72","author":"Wang","year":"2020","journal-title":"J Hepatol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01509-25","article-title":"Interferon alpha-inducible protein 27 (IFI27) inhibits hepatitis B virus (HBV) transcription through downregulating cellular transcription factor C\/EBP\u03b1","volume":"99","author":"Yu","year":"2025","journal-title":"J Virol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00236-10","article-title":"Inhibition of hepatitis B virus replication by MyD88 involves accelerated degradation of pregenomic RNA and nuclear retention of pre-S\/S RNAs","volume":"84","author":"Li","year":"2010","journal-title":"J Virol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101526","article-title":"Structure and function of the ecto-nucleotide pyrophosphatase\/phosphodiesterase (ENPP) family: Tidying up diversity","volume":"298","author":"Borza","year":"2022","journal-title":"J Biol Chem"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nature09907","article-title":"A diverse range of gene products are effectors of the type I interferon antiviral response","volume":"472","author":"Schoggins","year":"2011","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1007\/s00705-023-05949-6","article-title":"ENPP1 inhibits the transcription activity of the hepatitis B virus pregenomic promoter by upregulating the acetylation of LMNB1","volume":"169","author":"Ma","year":"2024","journal-title":"Arch Virol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001149","article-title":"Better together: the role of IFIT protein-protein interactions in the antiviral response","volume":"99","author":"Mears","year":"2018","journal-title":"J Gen Virol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1159\/000353220","article-title":"Interferon-induced proteins with tetratricopeptide repeats 1 and 2 are cellular factors that limit hepatitis B virus replication","volume":"6","author":"Pei","year":"2014","journal-title":"J Innate Immun"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2010.0101","article-title":"The ISG56\/IFIT1 gene family","volume":"31","author":"Fensterl","year":"2011","journal-title":"J Interferon Cytokine Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/nri3344","article-title":"The broad-spectrum antiviral functions of IFIT and IFITM proteins","volume":"13","author":"Diamond","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2008.112797","article-title":"The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection","volume":"67","year":"2017","journal-title":"J Hepatol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2016.12.006","article-title":"Impaired expression and function of TLR8 in chronic HBV infection and its association with treatment responses during peg-IFN-\u03b1-2a antiviral therapy","volume":"41","author":"Deng","year":"2017","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1186\/s12985-023-02119-7","article-title":"Triple motif proteins 19 and 38 correlated with treatment responses and HBsAg clearance in HBeAg-negative chronic hepatitis B patients during peg-IFN-\u03b1 therapy","volume":"20","author":"Luo","year":"2023","journal-title":"Virol J"},{"key":"B37","doi-asserted-by":"publisher","first-page":"13383","DOI":"10.1038\/s41598-017-13747-9","article-title":"Switching to PegIFN\u03b1-2b leads to HBsAg loss in patients with low HBsAg levels and HBV DNA suppressed by NAs","volume":"7","author":"Huang","year":"2017","journal-title":"Sci Rep"},{"key":"B38","doi-asserted-by":"publisher","first-page":"25","DOI":"10.14218\/jcth.2017.00072","article-title":"HBsAg loss with Peg-interferon Alfa-2a in hepatitis B patients with partial response to nucleos(t)ide analog: New Switch Study","volume":"6","author":"Hu","year":"2018","journal-title":"J Clin Transl Hepatol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.14218\/jcth.2019.00016","article-title":"A potential functional cure in Chinese HBeAg-negative chronic hepatitis B patients treated with Peg-interferon Alpha-2a","volume":"7","author":"Chen","year":"2019","journal-title":"J Clin Transl Hepatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23722","article-title":"Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels","volume":"52","author":"Rijckborst","year":"2010","journal-title":"Hepatology"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.12.007","article-title":"Validation of a stopping rule at week 12 using HBsAg and HBV DNA for HBeAg-negative patients treated with peginterferon alfa-2a","volume":"56","author":"Rijckborst","year":"2012","journal-title":"J Hepatol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26436","article-title":"Response-guided peginterferon therapy in hepatitis B e antigen-positive chronic hepatitis B using serum hepatitis B surface antigen levels","volume":"58","author":"Sonneveld","year":"2013","journal-title":"Hepatology"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2025.03.018","article-title":"EASL clinical practice guidelines on the management of hepatitis B virus infection","volume":"83","year":"2025","journal-title":"J Hepatol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-024-10666-6","article-title":"Predictive models for functional cure in patients with CHB receiving PEG-IFN therapy based on HBsAg quantification through meta-analysis","volume":"18","author":"Zhang","year":"2024","journal-title":"Hepatol Int"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy270","article-title":"Serum HBV RNA as a predictor of Peginterferon Alfa-2a response in patients with HBeAg-positive chronic hepatitis B","volume":"218","author":"van B\u00f6mmel","year":"2018","journal-title":"J Infect Dis"},{"key":"B46","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1111\/apt.14376","article-title":"Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection","volume":"47","author":"Mak","year":"2018","journal-title":"Aliment Pharmacol Ther"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1796228\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T05:39:58Z","timestamp":1781069998000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1796228\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2026.1796228"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1796228","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]},"article-number":"1796228"}}