Targeting Psoriasis at the Source: New Evidence for Interferon Receptor Therapies

Despite significant progress in psoriasis therapeutics, many patients continue to experience relapse, inadequate response, or limited options for difficult-to-treat subtypes. A recent integrative study in Biomedicines offers new precision targets by combining large-scale plasma proteomics, genetic association data, and transcriptomic profiling to identify causal proteins driving psoriasis pathogenesis.

By integrating data from over 400,000 individuals across multiple biobanks, the authors identified 13 plasma proteins with significant associations to psoriasis risk, with interferon lambda receptor 1 (IFNLR1) and interferon gamma receptor 2 (IFNGR2) emerging as top candidates. These proteins were not only genetically linked to disease onset, but they also exhibited disease-specific expression patterns and structural compatibility with approved immunomodulatory drugs.

The study began with a rigorous Mendelian randomization framework, using cis-pQTLs from the UK Biobank Pharma Proteomics Project to identify proteins causally associated with psoriasis. Replication across datasets from Iceland and the EPIC-Norfolk cohort confirmed these findings. Importantly, Bayesian colocalization analyses revealed that IFNLR1, IFNGR2, APOF, and TDRKH shared the same causal variants as psoriasis traits, ruling out confounding from linkage disequilibrium or horizontal pleiotropy. This genetic validation was further strengthened by reverse MR analyses and statistical controls that excluded reverse causation.

What distinguishes IFNLR1 and IFNGR2 is the convergence of multiple lines of evidence. Single-cell RNA sequencing of psoriatic versus normal skin revealed that both proteins are highly and specifically expressed in T cells within psoriatic lesions—a finding absent in healthy tissue. This spatial and cellular specificity grounds the genetic association in a functionally relevant context. While other identified proteins, including APOF, TDRKH, and DDR1, also showed subtype-specific or cell-type restricted expression, the interferon receptors demonstrated the clearest path from genetic variant to disease phenotype to therapeutic potential.

Functionally, both IFNLR1 and IFNGR2 are embedded within the JAK-STAT signaling pathway, a central axis in immune modulation and the target of several approved psoriasis therapies. The investigators performed protein-protein interaction analyses showing that IFNLR1 directly interacts with TYK2, JAK1, JAK3, and IL12B—nodes that are already targeted by drugs like deucravacitinib, upadacitinib, and ustekinumab. IFNGR2 shares many of these same connections and is a known receptor for interferon-gamma, which drives TNF-α expression and other inflammatory mediators implicated in psoriasis pathogenesis.

To translate these insights into pharmacologic terms, the team conducted molecular docking simulations. IFNLR1 and IFNGR2 demonstrated favorable binding affinities with deucravacitinib and ruxolitinib, with binding energies below −5 kcal/mol. This level of predicted binding stability suggests both proteins could serve as effective therapeutic targets, either via repurposing of existing drugs or as scaffolds for novel drug development.

Additional proteins identified in this study, such as APOF and TDRKH, expand the landscape of possible therapeutic exploration. APOF, typically linked to lipid metabolism and cardiovascular risk, showed exclusive expression in psoriatic but not normal skin, aligning with known comorbidities of psoriasis such as atherosclerosis. TDRKH, although previously associated with reproductive biology, demonstrated psoriasis-specific expression in T cells, raising novel questions about its immunologic roles. While the functional relevance of these proteins remains less defined, their consistent genetic association and expression specificity position them for further experimental work.

Taken together, this work suggests that IFNLR1 and IFNGR2 are not just biologically relevant to psoriasis pathogenesis—they also seem structurally and pharmacologically poised for therapeutic targeting. Their involvement in the interferon signaling axis, T cell-specific expression in psoriatic tissue, and demonstrated binding affinity with existing immunomodulators make them particularly compelling candidates for future clinical trials. While further validation, particularly in non-European populations and functional experiments, remains necessary, the findings represent a strong foundation for precision drug development in psoriasis.

In a therapeutic landscape where many patients still fail to achieve sustained remission, this study provides a roadmap for integrating human genetics, molecular biology, and computational pharmacology to develop next-generation interventions tailored to the immunopathology of psoriasis.

Reference
Wang H, Wang C, Qin R, et al. Integrative analysis of plasma proteomics and transcriptomics reveals potential therapeutic targets for psoriasis. Biomedicines. 2025;13(6):1380. doi:10.3390/biomedicines13061380