Lutein Targets TLR4 as a Potential Immunotherapeutic Strategy for Treatment of Doxorubicin-Induced Cardiomyopathy

Toll-like receptor 4 is an immune receptor associated with inflammatory diseases, including cardiac conditions. Lutein, a natural carotenoid with potent anti-inflammatory effects, protects against coronary heart disease and other cardiovascular issues. We aimed to explore its potential cardioprotective effects against doxorubicin-induced cardiomyopathy (DIC), focusing on the TLR4/NF-κB and JAK/STAT pathways. We compared its effects with olmesartan, commonly used to manage DIC. This study was performed on five groups of rats: control, doxorubicin (Dox)-treated, lutein-treated, olmesartan-treated, and combination-treated groups. Induction of DIC was performed using Dox (4.5 mg/kg every other day) for ten days. In treatment groups, lutein (50 mg/kg/day) or olmesartan (10 mg/kg/day) was administered for 10 days alongside Dox, while the combination treatment group co-administered lutein (50 mg/kg/day) and olmesartan (10 mg/kg/day) for the same duration alongside Dox. The results indicated that lutein protected cardiomyocytes from Dox-induced histopathological changes, including myocardial fiber disorganization, vascular congestion, and perivascular edema. It decreased the levels of TLR4, NF-κB, p-JAK2, and p-STAT1/3 relative to the Dox group, exhibiting an anti-inflammatory effect through suppression of the TLR4/NF-κB and JAK/STAT pathways. It also had regulatory effects on Akt/mTOR signaling, another pathway linked to TLR4 activation. In comparison to olmesartan, lutein had superior effects on IL-6/JAK2/STAT1/NF-κB and Akt/mTOR levels. Combination treatment also demonstrated cardioprotective effect at histopathological, biochemical, and molecular levels, being more effective than olmesartan on IL-6/NF-κB and Akt/mTOR levels. Moreover, Lutein administration alongside Dox showed anti-inflammatory and cardioprotective effects against DIC, suggesting it as a promising adjunct therapy, either alone or with olmesartan.