{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nIFNL4 was identified as a novel type‐III interferon generated by a frameshift‐creating dinucleotide variant upstream of IFNL3. This unique gene, present only in carriers of the IFNL4–ΔG allele, is induced in primary human hepatocytes upon viral mimicry and, when overexpressed, potently activates JAK–STAT signaling to induce interferon‐stimulated genes (ISGs). Comparative studies in human cells and mammalian orthologs confirm that, despite its relatively poor secretion, IFNL4 is biologically active and conserved across species."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNotably, IFNL4 displays paradoxical clinical associations. Although it has intrinsic antiviral properties, its expression correlates with impaired clearance of hepatitis C virus (HCV), slower viral decay during direct‐acting antiviral treatments, and poorer treatment responses. Specific coding variants—such as the P70S substitution—modulate its activity, with the fully active form driving high basal ISG expression that may render hepatocytes refractory to further interferon stimulation. Moreover, genetic variations in the IFNL3–IFNL4 locus are linked not only to altered inflammation and fibrosis in the liver but also to differential susceptibility to other viruses including HIV, cytomegalovirus and even SARS‐CoV‑2 infection."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, IFNL4 is distinguished by its non‐canonical regulation. Its messenger RNA is only modestly induced by viral infection, and alternative splicing as well as suboptimal translation signals limit the production of secreted protein. Instead, IFNL4 accumulates intracellularly where it rapidly induces negative regulators (for instance, SOCS1 and USP18), thereby attenuating subsequent interferon responses. Evolutionary and comparative analyses further reveal that despite its antiviral capability, selective pressures have favored IFNL4 inactivation in human populations—a phenomenon that may help explain its counterintuitive role in chronic liver disease progression, immune modulation and even cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ludmila Prokunina-Olsson, Brian Muchmore, Wei Tang, et al. 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