Causality Dilemma: Reassessing the Role of Interferon Signature Genes in Human Disease

Interferons (IFNs) are synonymous with mobilizing cell-intrinsic defenses against microbial infection through the induction of interferon-stimulated genes (ISGs). Omics-based profiling has revealed that ISGs also dominate the transcriptional signature of a wide range of human disease conditions, including cancer, autoimmune and autoinflammatory disorders, and even normal aging. The ubiquity of the IFN signature means it is often interpreted as a biomarker for upstream inflammation, with little consideration given to how persistent ISG induction might influence downstream cellular and tissue physiology. However, the identification of endogenous targets for a growing number of ISG-encoded effectors has broadened our appreciation for the function of these genes—both in terms of how self-defense is achieved but also for the potential implications emanating from their prolonged induction. The same host-directed mechanisms that provide broad antimicrobial protection can, depending on context, either preserve tissue homeostasis or contribute to chronic inflammation and tissue dysfunction. In this perspective, we revisit the longstanding question of IFN causality in disease and argue that ISGs should be viewed as active participants in pathogenesis rather than passive markers of inflammatory activity. By examining disease-specific ISG expression patterns and synthesizing emerging evidence for the endogenous functions of ISGs, many of which converge on mitochondrial regulation, we propose a framework in which the composition of an IFN signature associated with a diseased tissue plays a major role in dictating whether inflammation is resolved or perpetuated.