Emerging evidence identifies HMGB1 as a critical regulator of chemoresistance in small cell lung cancer (SCLC) by linking DNA damage responses with selective autophagic degradation of nuclear components.
In small cell lung cancer, elevated HMGB1 expression correlates with poor prognosis and reduced sensitivity to chemotherapy. Rather than acting solely as a chromatin-associated DNA-binding protein or extracellular alarmin, HMGB1 directly influences the fate of the DNA damage sensor PARP1.
This interaction facilitates the selective removal of PARP1 from sites of DNA damage through nucleophagy, promoting PARP1 turnover and allowing tumor cells to better tolerate chemotherapy-induced genomic stress.
Importantly, disrupting the PARP1–LC3 interaction or treating cells with PARP inhibitors (PARPi) significantly reduces chemoresistance, supporting nucleophagy as a therapeutically actionable pathway. These findings also suggest that HMGB1 expression may serve as a predictive biomarker for PARPi responsiveness in patients with SCLC.
This work expands the biological functions of HMGB1 beyond its established roles in chromatin dynamics, inflammation, and extracellular signaling, positioning it as a key regulator of nuclear quality control mechanisms that influence therapeutic response
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