<p>Climate-induced heat stress poses a major challenge to small ruminant productivity in arid and semi-arid regions, affecting growth, metabolism, and immune function. This study examined tissue-specific molecular responses to chronic heat stress in lambs by evaluating the expression of key genes associated with inflammation, oxidative stress, proteostasis, and muscle function in the liver and skeletal muscle. Twenty-four lambs were reared at two climatically contrasting field sites (thermoneutral vs. high-THI) for 42 days. In the liver, exposure to the heat-stressed environment was associated with decreased SOD1 expression alongside increased FOXO3 and pro-inflammatory IL-6, while TNF-α and PPARγ were significantly lower. In muscle, a different profile emerged: heat shock proteins (HSP70, HSP90) and the apoptotic marker CASP3 were strongly upregulated, MYOD was suppressed, and ACTB3 remained stable. These results suggest candidate tissue-specific transcriptional signatures associated with impaired muscle regeneration and enhanced proteotoxic stress, although the field-based design confounds thermal load with other site-specific factors and does not permit causal attribution. Composite gene expression ratios—such as SOD1/IL-6 and FOXO3/TNF-α—were elevated under heat stress and negatively correlated with rectal temperature, indicating a potential role as candidate molecular indices associated with thermal response. Principal component analysis further distinguished control and heat-stressed animals based on transcriptional profiles. These findings highlight the coordinated yet divergent molecular strategies employed by liver and muscle tissues under prolonged thermal stress. The study provides preliminary, hypothesis-generating insight into gene-level responses associated with contrasting thermal environments and identifies candidate molecular targets warranting further validation in controlled designs before application to selection or intervention strategies.</p>