Activation of Erk/STAT/Akt/JAK signaling. Heme treatment upregulated the Erk1/2 (p44/42 MAPK; A), phospho STAT3 (B), and phospho Akt (C) pathways. Free heme also upregulated the PGC1α (D) in WT lung tissue. Notably, the absence of MKK3 attenuated the activation of Erk, Stat, Akt, and PGC1α. JAK2, upstream of p38, is activated by heme but was not affected in the MKK3 KO (E). Black dots represent without heme treatment, and red dots represent with heme treatment. KO, knockout; WT, wild-type. Data represented as means ± SD, n = 6, *P < 0.05 vs. WT, #P < 0.05 vs. WT + Heme by one-way ANOVA with following Bonferroni multiple comparison test.