Inhibiting HuR-Mediated mRNA Stabilization Attenuates Psoriasis-Like Inflammation in Preclinical Models.

Purpose: Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferative keratinocytes and activated Th17/Th1 lymphocytes, which sustain a self-perpetuating cycle by releasing pro-inflammatory cytokines. The RNA-binding protein (RBP) Human Antigen R (HuR) stabilizes many of these cytokine mRNAs, contributing to disease progression. This study aims to investigate the role of the HuR protein in psoriasis and modulate its activity to develop novel therapeutic strategies. Patients and Methods: We evaluated the effects of Human Antigen R (HuR) silencing on psoriatic markers in both patient-derived keratinocytes and lymphocytes. Furthermore, we identified novel HuR targets within a psoriatic context using enhanced Cross-Linking and ImmunoPrecipitation sequencing (eCLIP-seq) in psoriasis-like HaCaT cells. Finally, we investigated the pharmacological effects of the TM11, a Tanshinone-mimic (TM) molecule, in an in vivo mouse model and an ex vivo 3D human skin model. Results: Studies on HuR function in HaCaT cells and in patient-derived primary keratinocytes and lymphocytes, demonstrated that keratinocyte proliferation and lymphocyte activation and differentiation are both dependent on HuR. In psoriatic-like HaCaT cells, eCLIP-seq data identified novel psoriatic-related HuR targets, and its mRNA-stabilizing activity was confirmed. Treatment with TM11, that competes with HuR-mRNA binding, reduced keratinocyte proliferation and psoriasis proteins (Cyclin B, Survivin, S100A7, eFABP), and almost suppressed T-cell activation (CD25⁺CD69⁺) and Th17/Th1 cytokine production. In vivo, TM11 reduced psoriasis-like symptoms in Imiquimod-treated mice, reducing Psoriasis Area and Severity Index (PASI) scores, systemic inflammation and histological alterations. In ex vivo InflammaSkin Conclusion: Overall, these findings highlight HuR as a key driver of psoriasis pathogenesis and provide preclinical evidence that pharmacological modulation of HuR activity, by TM11 treatment, could provide a conceptual therapeutic rationale for psoriasis, potentially contributing to the reduction of keratinocyte hyperproliferation and immune activation while favouring the restoration of skin homeostasis. However, further preclinical and clinical validation will be required to establish its translational feasibility.