Background: Pulmonary fibrosis (PF), the end-stage manifestation of interstitial lung disease, is defined by excessive extracellular matrix deposition and alveolar destruction. Activated fibroblasts, the primary matrix producers, rely heavily on dysregulated glucose metabolism for their activation. While Salt Inducible Kinase 2 (SIK2) regulates glycolytic pathways in oncogenesis, its specific contributions to fibroblast activation and therapeutic potential in PF pathogenesis remain undefined. This study elucidates the functional role of SIK2 in PF and assesses its viability as a therapeutic target. Methods: SIK2 expression/localization in fibrosis was assessed by Western blot and immunofluorescence. Fibroblast-specific Sik2 KO mice evaluated effects on bleomycin-induced fibrosis. SIK2’s role in fibroblast activation and glucose metabolism impact (enzyme expression, metabolism assays, metabolites) were tested. SIK2 inhibitors were screened and evaluated therapeutically in fibrosis models. Results: It demonstrated significant SIK2 upregulation, specifically within activated fibroblasts of fibrotic lungs from both PF patients and murine models. Functional assays demonstrated that SIK2 is crucial for fibroblast activation, proliferation, and migration. Mechanistically, SIK2 enhances fibroblast glucose metabolism by increasing the expression of glycolysis-related enzymes. Additionally, this study demonstrated that the SIK2 inhibitor YKL06-061 effectively inhibited PF in both bleomycin and FITC-induced PF mouse models with the preliminary safety profile. Furthermore, we identified a novel therapeutic application for the clinically approved drug fostamatinib, demonstrating it inhibits fibroblast activation via SIK2 targeting and alleviates PF in mice. Conclusions: Our findings highlight SIK2 as a promising therapeutic target and provide compelling preclinical evidence for two distinct anti-fibrotic strategies with significant potential for future PF treatment.

Idiopathic pulmonary fibrosis (IPF) is a progressive, age-related lung disease with few modifiable risk factors. While healthy dietary patterns have been associated with reduced risk of chronic diseases, their impact on IPF remains unclear. This study investigated the relationship between adherence to healthy dietary patterns and incident IPF and explored whether phenotypic age acceleration mediates this association. We analyzed 196,473 participants from the UK Biobank. Dietary intake was assessed via repeated 24 -h recall questionnaires, and adherence scores were calculated for the DASH, MEDAS, and MIND dietary patterns. Cox proportional hazards models were used to estimate the association between dietary scores and incident IPF. Mediation analysis was conducted to examine the role of phenotypic age acceleration. During a median follow-up of 12.4 years, 516 IPF cases were identified. Higher adherence to all three dietary patterns was significantly associated with a reduced risk of IPF. In fully adjusted models, hazard ratios for the highest vs. lowest quartiles were 0.75 (95% CI: 0.59-0.95) for DASH, 0.53 (0.37-0.75) for MEDAS, and 0.66 (0.51-0.86) for MIND. Phenotypic age acceleration partially mediated these associations. Higher dietary scores were associated with a lower risk of incident IPF, partially mediated by reduced phenotypic age acceleration. These findings suggest that promoting healthy eating habits may contribute to reducing age-related lung disease burden in older adults.

Pulmonary fibrosis (PF) is an irreversible and lethal lung disease characterized by progressive scarring lacking safe and effective treatment options. Rece