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ABSTRACT Methionine (Met) and cysteine (Cys) are nutrients in broiler diets, responsible for strengthening protein synthesis, immunity, and metabolic regulation. To estimate the ideal digestible Met + Cys:digestible Lysine (Lys) ratio for broilers under a lipopolysaccharide (LPS) inflammatory challenge, 384 male broilers were distributed in a completely randomized 4×2 factorial design, with four ratios of dig. Met + Cys:dig. Lys (0.69, 0.73, 0.77, and 0.81) and two conditions (with or without challenge). Each treatment had eight replicates, with six birds per experimental unit (EU). The evaluated parameters included broilers’ weight gain (WG), feed intake (FI), and feed conversion ratio (FCR); jejunum mRNA transcript levels of nuclear factor kappa-B (NF-Κb), glutathione peroxidase (GPX), superoxide dismutase (SOD), glutathione synthetase (GSS), and methionine adenosyltransferase 2 (MAT2); relative weights of liver and spleen, and fat mass (%) and lean mass (%). A linear regression model would estimate the ideal ratio if an effect had occurred. No interaction (p>0.05) was observed between the factors for all the data, nor did the different ratios had any effect (p>0.05) either. LPS-administered exhibited reduced performance, heavier liver and spleen, and lower GSS expression. Hence, the lowest dig Met + Cys:dig Lys ratio (0.69) was sufficient to maintain the performance parameters, the relative weight of lymphoid organs, fat and lean mass, and NF-Kb, GPX, SOD, GSS, MAT2, and CBS mRNA transcript levels in the jejunum. (Met Cys (Cys diets synthesis immunity regulation Cysdigestible (Lys LPS (LPS challenge 38 42 4 4× design Cysdig. Cysdig 0.69, 069 0 69 (0.69 073 73 0.73 077 77 0.77 0.81 081 81 challenge. . challenge) replicates EU. EU (EU) WG, WG , (WG) FI, FI (FI) FCR (FCR) kappaB kappa B NFΚb, NFΚb NF Κb (NF-Κb) GPX (GPX) SOD (SOD) (GSS) MAT2 MAT (MAT2) spleen % (% %. occurred p>0.05 p005 p 05 (p>0.05 data either LPSadministered administered expression Hence 0.69 organs NFKb, NFKb Kb, Kb NF-Kb 3 06 6 (0.6 07 7 0.7 0.8 08 8 (EU (WG (FI (FCR (NF-Κb (GPX (SOD (GSS (MAT2 ( p>0.0 p00 (p>0.0 0.6 (0. 0. (MAT p>0. p0 (p>0. (0 p>0 (p>0 p> (p> (p