Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM), a progressive pulmonary disease exclusively affecting females, is caused by defects or mutations in the coding gene tuberous sclerosis complex 1 (TSC1) or TSC2, causing the mammalian target of rapamycin complex 1 (mTORC1) activation and autophagy inhibition. Clinically, rapamycin shows limited cytocidal effects, and LAM recurs after drug withdrawal. In this study, we demonstrated that TSC2 negatively regulated the sphingolipid metabolism pathway and the expressions of sphingosine kinase 1 (SPHK1) and sphingosine-1-phosphate receptor 3 (S1PR3) were significantly elevated in LAM patient-derived TSC2-deficient cells compared to TSC2-addback cells, insensitive to rapamycin treatment and estrogen stimulation.

Targeting glucose-6-phosphate dehydrogenase by 6-AN induces ROS-mediated autophagic cell death in breast cancer.

Dysregulation of G6PD involved in the pentose phosphate pathway (PPP) is known to promote tumorigenesis. The PPP plays a pivotal role in meeting the anabolic demands of cancer cells. However, the detailed underlying molecular mechanisms of targeting the G6PD-regulated PPP in breast cancer remain unclear.

Niclosamide Ethanolamine Salt Alleviates Idiopathic Pulmonary Fibrosis by Modulating the PI3K-mTORC1 Pathway.

Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) deposited by myofibroblasts differentiated from pulmonary fibroblasts. More signalling pathways, including the PI3K-Akt-mTOR and autophagy pathways, are involved in IPF pathogenesis.