Cisplatin-induced hearing loss (CIHL) affects half a million cancer patients annually, but treatment strategies are limited. We have previously shown that honokiol, an antioxidant and otoprotective compound, upregulates mitochondrial sirtuin 3 (SIRT3) and protects against CIHL. In the present study, we investigated the molecular requirements of this protection using a Sirt3 knockout (Sirt3^-/-) mouse model. Our results showed that honokiol pre-treatment ameliorated auditory threshold shifts in both wild-type and Sirt3^-/- mice. Quantitative histological analysis showed that honokiol pre-treatment protected against cisplatin-induced synaptopathy. To explore the underlying molecular mechanisms, we performed RNA-seq on wild-type outer hair cells (OHCs). Cisplatin treatment resulted in a global transcriptomic downregulation, which was biased towards longer genes. Differential expression analysis showed that cisplatin treatment resulted in the downregulation of mitochondrial redox genes, such as Idh2 and Aldh2, a pattern that was reversed by honokiol pre-treatment. Computational transcription factor binding site analysis predicted that honokiol rescues chromatin-modifying pathways, while suppressing the ternary complex factor subfamily. Lastly, honokiol-only treatment proactively reinforced antioxidant defenses via Sod2 upregulation. Together, these results provide a comprehensive transcriptomic map of OHCs in the cisplatin background and highlight the clinical potential of honokiol to protect against CIHL.

High-resolution visualization of cochlear cisplatin distribution is essential for understanding its pharmacokinetics and ototoxicity. We employed synchrotron X-ray fluorescence microscopy (XFM) to map platinum (Pt) at sub-micron resolution. Adult male FVB mice received cisplatin (10 mg/kg) through intravenous (i.v.) or intraperitoneal (i.p.) administration. Cochleae were collected on days 1, 7, and 14, cryo-sectioned, and scanned using XFM. Cochlear Pt signal increased progressively through day 14. Notably, i.v. administration led to higher Pt levels than the i.p. route, with the highest increase observed in the organ of Corti on day 14. These results provided the first cell-specific mapping of cochlear Pt distribution and revealed a persistent Pt accumulation long after systemic cisplatin clearance from plasma. Although no significant hearing loss was detected on day 14, the distinct of Pt kinetics between administration routes highlighted critical disconnections in cispla-tin-induced hearing loss between clinical chemotherapy and current preclinical animal models.

Background/Objectives: Cisplatin induced hearing loss (CIHL) is a major global health sequela of chemotherapy, affecting over half a million cancer patients annually. We previously reported that honokiol, a multifunctional molecule compatible with cisplatin, protects against CIHL and upregulates sirtuin 3. Sirtuin family is composed of seven highly conserved while differentially expressed members which are critical enzymes for oxidative stress regulation in different cellular compartments. Therefore, this study aims to further verify the expression and upregulation of the entire sirtuin family during honokiol-mediated hearing protection against CIHL in a tumor-bearing mouse model. Methods: Adult female mice carrying mouse mammary tumor virus polyomavirus middle T agent oncogene were used. These mice developed palpable tumors automatically at the age of 70.8±10.3 days. CIHL was induced using a three-cycle (14 days/cycle) low-dose (4 mg/kg/day for 4 days per cycle, intraperitoneal injection) cisplatin treatment mimicking chemotherapy regimens. Honokiol (5-20 mg/kg) was administered one hour before cisplatin. Cochlear function was evaluated by auditory brainstem response threshold shifts and synaptic changes. Immunostaining and RT-qPCR were performed to verify the upregulation of sirtuin family members (1, 2, 3, 5, and 7) during these processes. Results: CIHL was observed at high-frequency range (24-32 kHz), which was mitigated by honokiol treatment. The optimal dose of honokiol for oto-protection and animal survival was 10 mg/kg. Fluorescence signals of sirtuins 1, 2, 3, 5, and 7 increased in cochleae from honokiol-treated mice. RT-qPCR confirmed a significant upregulation of sirtuin 3 mRNA with honokiol treatment. Conclusions: Sirtuin family upregulation was involved in honokiol-mediated hearing protection against CIHL. The dose-response curve of honokiol lays the foundation for potential translational applications for human studies.

Objective: Given growing recognition that social determinants of health influence cancer outcomes and functional status, we sought to examine associations between social vulnerability, measured by CDC's Social Vulnerability Index (SVI), and pretreatment swallowing function, quantified by Modified Barium Swallow Impairment Profiles (MBSImP), in patients with oropharyngeal squamous cell carcinoma (OPSCC). Study Design and Setting: Retrospective analysis of patients at Northwestern University with pretreatment MBSImP studies. Methods: MBSImP oral total (OT) and pharyngeal total (PT) scores were calculated, and SVI assigned to patient residential address at diagnosis. Associations between overall SVI, SVI subcomponents, clinical variables, and OT and PT scores were assessed using univariable and multivariable linear regression. Results: 149 OPSCC patients with median age 63 years; 83.9% were male, 89.9% White, and 91.9% p16+. On univariable analysis, SVI was significantly associated with higher (worse) OT ( β = 3.3; 95% CI: 1.8, 4.8; P < .001) and PT scores ( β = 3.6; 95% CI: 0.75, 6.4; P = .013). After multivariable adjustment, SVI remained independently associated with increased OT scores ( β = 2.3; 95% CI: 0.36, 4.2; P = .020); PT impairment was independently predicted by tumor subsite (tonsil vs. base of tongue: β = −1.8; 95% CI: −3.4, −0.28; P = .021). All four SVI domains were significantly linked to OT in univariable models. Conclusion: Social vulnerability independently predicts oral‐phase swallowing impairment in OPSCC patients, while tumor subsite primarily determines pharyngeal swallowing impairment. These findings highlight the need to consider social determinants in pretreatment assessment, as well as further research to clarify how social determinants impact swallowing outcomes to identify effective, targeted interventions for high‐risk groups.

Background/Objectives: Cisplatin-induced hearing loss (CIHL) is a major global health sequela of chemotherapy, affecting over half a million cancer patients annually. We previously reported that honokiol, a multifunctional molecule compatible with cisplatin, protects against CIHL and upregulates sirtuin 3. The sirtuin family is composed of seven highly conserved yet differentially expressed members that are critical enzymes for oxidative stress regulation in different cellular compartments. Therefore, this study aims to further verify the expression and upregulation of the entire sirtuin family during honokiol-mediated hearing protection against CIHL in a tumor-bearing mouse model. Methods: Adult female mice carrying the mouse mammary tumor virus polyomavirus middle T agent oncogene were used. These mice developed palpable tumors spontaneously at the age of 70.8 ± 10.3 days. CIHL was induced using a three-cycle (14 days/cycle) low-dose (4 mg/kg/day for 4 days per cycle, intraperitoneal injection) cisplatin treatment mimicking chemotherapy regimens. Honokiol (5–20 mg/kg) was administered one hour before cisplatin. Cochlear function was evaluated by auditory brainstem response threshold shifts and synaptic changes. Immunostaining and RT-qPCR were performed to verify the upregulation of sirtuin family members (1, 2, 3, 5, and 7) during these processes. Results: CIHL was observed in the high-frequency range (24–32 kHz), which was mitigated by honokiol treatment. The optimal dose of honokiol for oto-protection and animal survival was 10 mg/kg. Fluorescence signals of sirtuins 1, 2, 3, 5, and 7 increased in cochleae from honokiol-treated mice. RT-qPCR confirmed a significant upregulation of sirtuin 3 mRNA with honokiol treatment. Conclusions: Sirtuin family upregulation was involved in honokiol-mediated hearing protection against CIHL. The dose–response curve of honokiol lays the foundation for potential translational applications for human studies.