(A) Unsupervised hierarchical clustering (Euclidean) heatmap of differentially expressed genes (DEGs; fold-change [FC] > 1.5; false discovery rate [FDR] < 0.05) in AT2^I73T cells 3 days and 14 days after in vivo tamoxifen induction (n = 4 per group) versus AT2^WT cells (age-matched C57B6/J mice, n = 8 by popRNA-Seq). A subset of DEGs is highlighted. STRING network analysis shows downregulation of genes associated with primary metabolic processes and lipid metabolism and upregulation of genes associated with proliferation and ECM organization in AT2^I73T cells. (B) Reactome pathway analysis of DEGs in AT2^I73T cells at 3 days and 14 days after tamoxifen induction demonstrates differential regulation of multiple metabolic pathways. (C) Schematic of rate-limiting enzymes in glycolysis pathway and individual graphs of normalized popRNA-Seq counts for highlighted genes in 3-day and 14-day AT2^I73T and AT2^WT cells. (D) Western blot of AT2^WT and AT2^I73T cells at peak of inflammation (14 days) and fibrosis (28 days) with densitometric quantification (mean±SEM; n = 3 biological replicates) showing differential LDHA and LDHB protein abundance. (E) Extracellular lactate and glucose concentrations (μM) in 48-hour ex vivo cultures of AT2^I73T cells (28 days after in vivo tamoxifen) and AT2^WT cells, measured by YSI biochemistry analyzer and normalized to total protein content (mean±SEM; n = 3 or 4 biological replicates). (F) Intracellular glucose, lactate, and pyruvate concentrations from 40,000 flow-sorted AT2 cells, reported as ratios to WT mean concentration (mean±SEM; n = 4 biological replicates). *P < 0.05, **P < 0.005, ***P < 0.0005, ****P < 0.00005 by ordinary 1-way ANOVA.