Targeting FPR1 to prevent doxorubicin-induced cardiomyopathy

Background/Introduction Doxorubicin (DOX) is effective against cancer but can cause cardiotoxicity and immunosuppression, reducing its utility. Formyl peptide receptor-1 (FPR1) is essential for DOX-induced immunologic activation; however, a prevalent FPR1 variant (rs867228) diminishes this signaling, heightening chemoresistance [1]. In mice, Toll-like receptor 3 (TLR3) agonist poly-inosinic:cytidyl acid(pIC) can overcome this refractory phenotype [2]. Purpose We investigated whether FPR1 inhibition, coupled with TLR3 agonism via poly(I:C), protects against DOX-induced cardiomyopathy (DCM). We hypothesized that reduced FPR1 signaling prevents cardiac damage without undermining DOX’s anticancer effects. Methods Wild-type (WT) and FPR1-inhibited mice received weekly DOX (5 mg/kg/week, cumulative 15 mg/kg). Additional groups were also treated with the FPR1 inhibitor Cyclosporin H (CsH) or poly(I:C) thrice weekly for six weeks. Then, we performed echocardiography, histology, and biochemical assays. Results Six-weeks survival in DOX-treated FPR1-KO mice exceeds the WTs (96% vs. 70%, p≤0.001). DOX-treated WTs have reduced fractional shortening (43.1±1.56% vs. 29.1±2.12%, n=7). In contrast, FPR1-KO (43.8±1.2%) and CsH-treated mice (39.9±4.57%, n=4–13) maintain cardiac function with DOX, similarly to pIC-treated mice (39.3 ± 3.34%) (Fig. 1A). DOX induces myocardial fibrosis in WT mice (1.7±1.06% vs. controls: 0.5±0.09%, n=4–5), which is less in FPR1-KO mice (0.3±0.09%, n=5–6) (Fig. 1B). TUNEL-positive apoptotic cardiomyocytes increase in WT DOX-treated mice compared to controls (0,1±0,05% vs. 0,4±0,08%, n=7-8) and FPR1-KO mice (0,2±0,08%) (Fig. 1C). Also, activated caspase-3 (Cl-casp3) decreases in DOX-treated FPR1 KO mice compared to the WT (3,5±1,04 vs. 1,5±0,53, n=5) (Fig. 1D). WT mice treated with DOX show reduced complex IV activity (0.3±0.03 vs. 0.2±0.01, n=4), whereas FPR1-KO hearts maintain complex enzymatic IV activity (0.2±0.01 vs. 0.3 ± 0.01, n=4) (Fig. 1E). Complex I integrity decreases in WT DOX-treated mice (1±0,04 vs. 0,5±0,13, n=6) but is preserved in FPR1-KO mice (1±0,17, n=6) (Fig. 1F). Metabolomic analyses show enrichment of pathways related to alternative energy metabolism and oxidative stress management in FPR1-KO mice treated with DOX (P≤0.05) (Fig. 1G-H). Clonogenic assays on MCF-7 breast cancer cells indicate that DOX and pIC (18±5,18 and. 12,7±2,03, n=6) reduce colony formation compared to the WT (49,3±2,85). CsH+pIC administration successfully enhances DOX tumor cell eradication, differently from CsH+DOX (7±2,25 vs. 74,5±10,41, n=6), pinpointing FPR1 inhibition critical for neoplastic growth (Fig. 1J-K). Conclusion(s) FPR1 inhibition shields the heart from DOX-induced injury by sustaining cardiac function, metabolic flexibility, and survival pathways, without compromising DOX’s antitumor efficacy. Targeting FPR1 may offer a strategy to mitigate DOX cardiotoxicity while preserving its therapeutic benefits.