Autophagy is a conserved degradation pathway. Autophagy maintains cellular homeostasis in the cell by directing the clearance of old and abnormal proteins or organelles. However, autophagy dysregulates leads to many diseases. In addition, a key transcriptional modulator of the autophagy-lysosome system is transcription factor EB (TFEB). Interestingly, overexpression of TFEB results in an increased number of lysosomes, an increased rate of degradation of autophagy substrates, induction of mitophagy, and in specific disease states, halt disease progression.  Thus activation of TFEB is believed to have potential therapeutic utility for diseases with lysosomal dysfunction and cellular clearance abnormality such as heart failure, Parkinson’s disease, Alzheimer’s disease, and others. Hence, we will introduce an ERR agonist, SLU-PP-915.

SLU-PP-915 is an ERR pan-agonist, with an EC₅₀ value of approximately 400 nM for ERRα, ERRβ, and ERRγ.

In vitro, SLU-PP-915 (2.5 µM; 72 h) increases the gene and protein expression of transcription factor EB (TFEB) in neonatal rat ventricular myocytes (NRVMs). Moreover, SLU-PP-915 (5 µM) increases the expression of TFEB gene (at 3 h) and TFEB protein (at 72 h) in C₂C₁₂ cells. In addition, SLU-PP-915 (5 µM; 48 h or 72 h) increases the expression of PGC1a, p62, PDK4, CTSD, LAMP1, LAMP2 and MCOLN1 ERR target genes in C₂C₁₂ cells.

In vivo, SLU-PP-915 shows the cardiac protective effect in pressure overload-induced heart failure. In addition, SLU-PP-915 mainly through ERRγ activates a broad spectrum of metabolic genes and leads to an elevation in fatty acid metabolism and mitochondrial function. Thereby, SLU-PP-915 improves the pumping function in TAC-induced heart failure in vivo without affecting cardiac hypertrophy.

All in all, SLU-PP-915 is a hopeful agent for the activation of TFEB. SLU-PP-915 has potential application in maintaining oxidative metabolism and heart failure.

Reference:

[1] McKenna Losby, et al. bioRxiv. 2023 Mar 2. 

[2] Weiyi Xu, et al. bioRxiv. 2022 Feb 16.