Transcriptional Reprogramming Revealed in Degraded Mouse Liver RNA beyond Conventional RIN Thresholds

• We demonstrate a critical disconnect between RNA integrity (RIN) and the reliability of transcriptomic data in mouse liver. • Time-course clustering reveals that RNA degradation triggers a programmed, biologically coherent stress response. • Three core transcriptional programs are identified: rapid functional shutdown, acute alarm, and progressive immune activation. The RNA integrity number (RIN) is often regarded as a stringent gatekeeper in transcriptomics, frequently resulting in the exclusion of valuable clinical and field samples. We systematically challenged this prerequisite by simulating ex vivo degradation in mouse liver tissue. Although RIN values declined sharply with exposure to room temperature, the global transcriptome remained robust and showed no correlation with RIN. Importantly, our time-series analysis revealed that RNA degradation is not a source of random noise but a structured, biologically meaningful process. We identified three coordinated transcriptional programs: rapid functional shutdown, acute alarm response, and progressive immune activation. These findings demonstrate that data from low-RIN samples are not compromised but biologically informative. This study presents a novel framework for transcriptomics. RNA degradation is no longer viewed solely as a technical obstacle; instead, it has become a valuable tool for investigating organ-wide stress responses. Additionally, this approach helps maximize the utility of precious biobanked resources.