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Long non-coding RNAs (lncRNAs) play key roles in gene regulation. One potential regulation mechanism involves the formation of RNA•DNA:DNA triplexes. In these triplexes, the lncRNA binds in the major groove of a target DNA via Hoogsteen base pair formation. Here, we investigated the impact of the underlying RNA binding on the on the stability of the DNA duplex target to gain insights into the triplex stability at base pair resolution. Quantification of the temperature-dependent exchange of imino hydrogen atoms with solvent of the target DNA duplex allows determination of the changes of the stability of individual DNA duplex base pairs upon triplex formation. The data shown here investigates an antiparallel triplex, formed between the lncRNA hypoxia-inducible factor 1-alpha Antisense RNA 1 (HIF1α-AS1) and the DNA target Adrenomedullin (ADM), important in cardiovascular diseases. Triplex formation alters DNA structure and stability by affecting both hydrogen bonding strength and nucleobase-stacking interactions. These thermodynamic insights support bioinformatic methods to predict triplex stability and enhance our understanding of RNA•DNA:DNA triplex formation.