New insights into Baricitinib's immunomodulatory role in doxorubicin-induced cardiomyopathy: JAK/STAT and TLR-4/NF-κB pathways.

Baricitinib recently gained attention as a selective Janus kinase inhibitor, mediating cytokine signaling pathways and immune-inflammatory cascades. This research designed to explore the potential cardioprotective impact of baricitinib in doxorubicin-induced cardiomyopathy (DIC), tracking its immunomodulatory effect on the JAK/STAT and TLR-4/NF-κB signaling pathways. We also compared its effect with olmesartan, an angiotensin receptor blocker (ARB), which is one of the treatments used for DIC. Five groups were created out of male albino rats: normal control group, doxorubicin group, baricitinib treatment group, olmesartan treatment group, combination treatment group. Doxorubicin, baricitinib and olmesartan were taken with dosages of 4.5 mg/kg day after day IP (Cumulative dose = 22.5 mg/kg), 3 mg/kg/day PO, 10 mg/kg/day PO, respectively for 10 days. The results showed that baricitinib exerted cardioprotective effect on histopathological and biochemical levels compared to doxorubicin group. It also downregulated the activation of the JAK/STAT signaling pathway via significant decreases in p-JAK2 and p-STAT1/3 compared to doxorubicin group. It also downregulated the TLR-4/NF-κB signaling pathway via significant decreases in TLR-4 and NF-κB compared to doxorubicin group. For the first time, we elucidated baricitinib's cardioprotective role against DIC thought modulation of the JAK/STAT and TLR-4/NF-κB immune-inflammatory pathways. Moreover, baricitinib significantly downregulated the two signaling pathways with subsequent downregulation of downstream markers; IL-6, TNF-α, VEGF-α, and NO, which are involved in inflammation and angiogenesis associated with DIC. Olmesartan alone or in combination with baricitinib also exerted cardioprotection by downregulating the two signaling pathways, while baricitinib demonstrated superior anti-inflammatory effects. Thus, baricitinib shows promise in mitigating DIC.