TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis

Fei Li; Niv Vigder; David R. Ziehr; Mari Kamiya; Hung N. Nguyen; Diana E. Ferreyra Faustino; Aseel H. Khalil; Hilaire C. Lam; Matthew L. Steinhauser; Edy Y. Kim; William M. Oldham

doi:10.1172/jci.insight.199449

TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis

Fei Li,¹ Niv Vigder,² David R. Ziehr,³ Mari Kamiya,⁴ Hung N. Nguyen,⁴ Diana E. Ferreyra Faustino,¹ Aseel H. Khalil,¹ Hilaire C. Lam,¹ Matthew L. Steinhauser,⁵ Edy Y. Kim,² and William M. Oldham¹

Published April 23, 2026 - More info

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease driven by aberrant fibroblast-to-myofibroblast differentiation, which requires metabolic reprogramming. Here, we identify alanine as an essential metabolite for myofibroblast differentiation. Transforming growth factor–β1 (TGF-β) increases intracellular alanine levels through enhanced synthesis and import in both normal and IPF lung fibroblasts. Alanine synthesis is primarily mediated by glutamate-pyruvate transaminase 2 (GPT2), whose expression is regulated by the glutamine–glutamate–α-ketoglutarate axis. Inhibition of GPT2 depletes alanine and suppresses TGF-β-induced α-SMA and COL1A1 expression, which are rescued by exogenous alanine. We also identify solute carrier family 38 member 2 (SLC38A2) as a transporter for both alanine and glutamine, upregulated by TGF-β or alanine deprivation. SLC38A2 and GPT2 form a coordinated regulatory axis sustaining intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency impairs glycolytic flux and depletes tricarboxylic acid cycle intermediates, while alanine supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly under glutamine deprivation. Combined inhibition of alanine synthesis and uptake suppresses fibrogenic responses in fibroblasts and human precision-cut lung slices, highlighting dual metabolic targeting as a potential therapeutic strategy for fibrotic lung disease.

TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis

Fei Li,¹ Niv Vigder,² David R. Ziehr,³ Mari Kamiya,⁴ Hung N. Nguyen,⁴ Diana E. Ferreyra Faustino,¹ Aseel H. Khalil,¹ Hilaire C. Lam,¹ Matthew L. Steinhauser,⁵ Edy Y. Kim,² and William M. Oldham¹

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TGF-β coordinates alanine synthesis and import for myofibroblast differentiation in pulmonary fibrosis

Fei Li,1 Niv Vigder,2 David R. Ziehr,3 Mari Kamiya,4 Hung N. Nguyen,4 Diana E. Ferreyra Faustino,1 Aseel H. Khalil,1 Hilaire C. Lam,1 Matthew L. Steinhauser,5 Edy Y. Kim,2 and William M. Oldham1

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Fei Li,¹ Niv Vigder,² David R. Ziehr,³ Mari Kamiya,⁴ Hung N. Nguyen,⁴ Diana E. Ferreyra Faustino,¹ Aseel H. Khalil,¹ Hilaire C. Lam,¹ Matthew L. Steinhauser,⁵ Edy Y. Kim,² and William M. Oldham¹