Non-FASN off-target mRNAs with seed-region complementarity

Non-FASN off-target mRNAs with seed-region complementarity refers to a collective group of messenger RNA (mRNA) transcripts that are unintentionally downregulated by RNA interference (RNAi) or antisense therapies designed to target Fatty Acid Synthase (FASN). This phenomenon, known as seed-mediated off-target effects, occurs when the seed region of an siRNA—typically nucleotides 2 through 8—shares complementarity with the 3' untranslated regions (UTRs) of transcripts other than the intended FASN target, mimicking the natural regulatory mechanism of microRNAs (Jackson et al., 2003, Nature Biotechnology). These interactions can lead to significant changes in the cellular transcriptome, potentially causing unintended toxicity or confounding the interpretation of biological data during drug development (Birmingham et al., 2006, Nature Methods). Because FASN is a major therapeutic target in oncology and metabolic diseases like NASH, ensuring the specificity of nucleic acid-based inhibitors is a critical safety requirement. These off-target mRNAs do not constitute a single therapeutic target but rather represent a technical and safety challenge that must be managed through sequence optimization and rigorous transcriptomic screening. Consequently, they are classified as an incorrect target entry in a therapeutic context, as they are entities to be avoided rather than modulated for clinical benefit.

Other names

Seed-mediated off-targetsRNAi off-target transcriptsmiRNA-like off-target effectsNon-specific mRNA knockdown

Sequence-specific binding of an siRNA or ASO seed region (typically nucleotides 2-8) to the 3' untranslated region (UTR) of unintended mRNAs, leading to RISC-mediated degradation or translational repression.