Single‐Cell Dissection of the Biological Function and Molecular Features Underlying the Micropeptide LSMEM1 in Kidney

LSMEM1, an evolutionarily conserved micropeptide with extreme hydrophobicity (aliphatic index═113) and dynamic amphiphilicity (GRAVY═0.017), features a strong α‐helical transmembrane anchor (residues 64‐86). Single‐cell analysis reveals its critical role in renal lipid homeostasis. The leucine‐rich membrane protein modulates tubular lipid droplet accumulation, linking its unique biophysical properties to chronic kidney disease progression and potential therapeutic targeting. Abstract Advances in computational biology and large‐scale transcriptome analysis have revealed an increasing number of short open reading frames (sORFs) encoding functional peptides. These small proteins or micropeptides can function independently or exert their biological functions by binding to and/or regulating larger regulatory proteins. LSMEM1 (leucine rich single‐pass membrane protein 1, also known as C7orf53) has been found to be significantly upregulated in chronic kidney disease (CKD). In the present study, the molecular structure is aimed to elucidate and function of LSMEM1 and dissect its implications both in physiological and pathophysiological condition. Single‐cell transcriptome sequencing (scRNA‐seq) technology is used to examine the transcriptional state and biological processes of Lsmem1−/− mice kidneys. Experiments are conducted to verify these biological processes in both physiological and disease states. LSMEM1 is associated with cell injury, inflammation and lipid metabolism. Further, LSMEM1 plays a critical role in delaying CKD progression through regulating lipid droplet accumulation in proximal tubular epithelial cells. This study explores the function of the small protein LSMEM1 in physiological and disease development. LSMEM1 may be a novel revenue for targeted therapy for CKD. LSMEM1, an evolutionarily conserved micropeptide with extreme hydrophobicity (aliphatic index═113) and dynamic amphiphilicity (GRAVY═0.017), features a strong α-helical transmembrane anchor (residues 64-86). Single-cell analysis reveals its critical role in renal lipid homeostasis. The leucine-rich membrane protein modulates tubular lipid droplet accumulation, linking its unique biophysical properties to chronic kidney disease progression and potential therapeutic targeting. Abstract Advances in computational biology and large-scale transcriptome analysis have revealed an increasing number of short open reading frames (sORFs) encoding functional peptides. These small proteins or micropeptides can function independently or exert their biological functions by binding to and/or regulating larger regulatory proteins. LSMEM1 (leucine rich single-pass membrane protein 1, also known as C7orf53) has been found to be significantly upregulated in chronic kidney disease (CKD). In the present study, the molecular structure is aimed to elucidate and function of LSMEM1 and dissect its implications both in physiological and pathophysiological condition. Single-cell transcriptome sequencing (scRNA-seq) technology is used to examine the transcriptional state and biological processes of Lsmem1 −/− mice kidneys. Experiments are conducted to verify these biological processes in both physiological and disease states. LSMEM1 is associated with cell injury, inflammation and lipid metabolism. Further, LSMEM1 plays a critical role in delaying CKD progression through regulating lipid droplet accumulation in proximal tubular epithelial cells. This study explores the function of the small protein LSMEM1 in physiological and disease development. LSMEM1 may be a novel revenue for targeted therapy for CKD. Advanced Science, Volume 12, Issue 48, December 29, 2025.