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Background/Objectives: Neonatal respiratory distress syndrome (NRDS) is a heterogenous respiratory illness that mainly affects preterm neonates. It is characterized by insufficient production of pulmonary surfactant and impaired lung compliance. The lysophosphatidylcholine acyltransferase 1 (LPCAT1) enzyme has a crucial function in lipid remodeling through the conversion of lysophosphatidylcholine to phosphatidylcholine, the major component of pulmonary surfactant. In this research, we aimed to investigate the association of the LPCAT1*rs9728 variant with NRDS susceptibility using hereditary analysis and bioinformatic approaches. Methods: The LPCAT1 (rs9728; c.*1668T>C) variant was characterized among 100 preterm neonates with RDS and 100 non-RDS neonates utilizing the TaqMan SNP genotyping assay. Logistic regression analysis was performed to identify the risk factors of respiratory distress syndrome. The functional mechanism of the LPCAT1 gene was elucidated using bioinformatic approaches. Results: The LPCAT1*rs9728 C/C genotype was significantly associated with a 78% reduced risk of NRDS (OR = 0.22, p = 0.027), although the minor C allele did not attain a significant finding (OR = 0.83, p = 0.416). Apgar score and Silverman–Andersen respiratory severity score (RSS) were statistically significant with prematurity classes (p < 0.05). Additionally, gestational age and birth weight were considered independent risk factors in the progression of RDS among preterm neonates. Conclusions: This research exhibited a significant difference between the LPCAT1 (rs9728; c.*1668T>C) variant and reduced risk against the development of RDS among preterm neonates. The rs9728*C/C genotype revealed a significant association with decreased risk of NRDS compared to non-RDS neonates.

: Neonatal respiratory distress syndrome (NRDS) is a heterogenous respiratory illness that mainly affects preterm neonates. It is characterized by insufficient production of pulmonary surfactant and impaired lung compliance. The lysophosphatidylcholine acyltransferase 1 (LPCAT1) enzyme has a crucial function in lipid remodeling through the conversion of lysophosphatidylcholine to phosphatidylcholine, the major component of pulmonary surfactant. In this research, we aimed to investigate the association of the *rs9728 variant with NRDS susceptibility using hereditary analysis and bioinformatic approaches. : The (rs9728; c.*1668T>C) variant was characterized among 100 preterm neonates with RDS and 100 non-RDS neonates utilizing the TaqMan SNP genotyping assay. Logistic regression analysis was performed to identify the risk factors of respiratory distress syndrome. The functional mechanism of the gene was elucidated using bioinformatic approaches. : The rs9728 C/C genotype was significantly associated with a 78% reduced risk of NRDS (OR = 0.22, = 0.027), although the minor C allele did not attain a significant finding (OR = 0.83, = 0.416). Apgar score and Silverman-Andersen respiratory severity score (RSS) were statistically significant with prematurity classes ( < 0.05). Additionally, gestational age and birth weight were considered independent risk factors in the progression of RDS among preterm neonates. : This research exhibited a significant difference between the (rs9728; c.*1668T>C) variant and reduced risk against the development of RDS among preterm neonates. The rs9728*C/C genotype revealed a significant association with decreased risk of NRDS compared to non-RDS neonates.