Curcumol, a natural product isolated from the traditional Chinese medicine Rhizoma curcumae, possesses various potential therapeutic values in many diseases. However, evidence of its toxicological profile is currently lacking. In this study, a repeated toxicity study of curcumol was conducted for the first time. SD rats were exposed to doses of 250, 500, 1000 mg/kg in a selected dose formulation for 28 days through oral administration. The potential toxic effects of curcumol on the blood system were observed and further validated in vivo and in vitro. Moreover, other hematology and biochemistry parameters as well as the weight of organs were altered, but no related histopathological signs were observed, indicating these changes were not regarded as toxicologically relevant. Our current findings provide a complete understanding of the safety profile of curcumol, which may contribute to its further study of investigational new drug application.

Hu7691 represents a novel Pan-Akt kinase inhibitor, demonstrating excellent selectivity towards non-AGC kinase families and pronounced inhibitory effects on the proliferation of multiple tumor cell lines. However, there is currently a notable absence of in vivo toxicological research evidence concerning Hu7691. This study represents the first investigation into the 14-day repeated-dose toxicity of Hu7691 in male and female Sprague Dawley (SD) rats. Male rats were administered daily doses of 12.5, 50, 100, and 150 mg/kg/day, while female rats received doses of 12.5, 25, 50, and 75 mg/kg/day for 14 consecutive days. Hematological assessments, organ weights, and histopathological examinations revealed corresponding alterations, suggesting potential target organs for toxicity including the spleen, thymus, and gastrointestinal tract. It is worth noting that the test substance may also impact the liver, kidneys, heart, and ovaries. The No Observed Effect Level (NOAEL) was determined to be no greater than 12.5 mg/kg/day. Based on the observed gender-related toxicity differences in preliminary trials, it is recommended that the high dose reference dose for male animals in formal experiments should not be less than 100 mg/kg/day, while for female animals, it should be less than 50 mg/kg/day.

Hu7691 represents a novel Pan-Akt kinase inhibitor, demonstrating excellent selectivity towards non-AGC kinase families and pronounced inhibitory effects on the proliferation of multiple tumor cell lines. However, there is currently a notable absence of in vivo toxicological research evidence concerning Hu7691. This study represents the first investigation into the 14-day repeated dose toxicity of Hu7691 in male and female Sprague-Dawley (SD) rats. Male rats were administered daily doses of 12.5, 50, 100, and 150 mg/kg, while female rats received doses of 12.5, 25, 50, and 75 mg/kg for 14 consecutive days. Hematological assessments, organ weights, and histopathological examinations revealed corresponding alterations, suggesting potential target organs for toxicity including the spleen, thymus, and gastrointestinal tract. It is worth noting that the test substance may also impact the liver, kidneys, heart, and ovaries. The No Observed Effect Level (NOAEL) was determined to be no greater than 12.5 mg/kg. Based on the observed gender-related toxicity differences in preliminary trials, it is recommended that the high dose reference dose for male animals in formal experiments should not be less than 100 mg/kg, while for female animals, it should be less than 50 mg/kg.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is widely used for the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer. However, cutaneous toxicity remains a frequent adverse event, and its underlying molecular mechanisms remain poorly understood.In this study, we investigated osimertinib-induced cutaneous toxicity using HaCaT keratinocytes exposed to osimertinib (0.5 μM) and C57BL/6 mice treated with osimertinib (50 mg/kg/day for 42 consecutive days), with or without cryptotanshinone (10, 20, or 40 mg/kg/day). Osimertinib exposure induced inflammatory activation and epidermal dysfunction in mouse skin. In keratinocytes, DLX3 exhibited a biphasic response, with early induction followed by progressive depletion after prolonged exposure. DLX3 deficiency increased susceptibility to osimertinib-induced apoptosis, whereas osimertinib accelerated DLX3 protein turnover through a lysosome-associated process.Osimertinib-induced DLX3 depletion was accompanied by increased STAT3 phosphorylation and alterations in autophagy–lysosome-associated markers. Cryptotanshinone suppressed STAT3 phosphorylation, restored DLX3 protein abundance, and reduced osimertinib-induced apoptosis, DNA damage, and inflammatory responses. Loss of DLX3 weakened the protective effects of cryptotanshinone. In mice, cryptotanshinone alleviated osimertinib-induced skin lesions, epidermal injury, apoptosis, mast cell infiltration, and systemic inflammation.Collectively, these findings identify progressive DLX3 depletion, accompanied by STAT3 activation and autophagy–lysosome-related alterations, as a potential mechanism underlying osimertinib-induced cutaneous toxicity and suggest that preservation of DLX3 protein homeostasis may represent a strategy for mitigating drug-induced skin injury.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is widely used for the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer. However, cutaneous toxicity remains a frequent adverse event, and its underlying molecular mechanisms remain poorly understood.In this study, we investigated osimertinib-induced cutaneous toxicity using HaCaT keratinocytes exposed to osimertinib (0.5 μM) and C57BL/6 mice treated with osimertinib (50 mg/kg/day for 42 consecutive days), with or without cryptotanshinone (10, 20, or 40 mg/kg/day). Osimertinib exposure induced inflammatory activation and epidermal dysfunction in mouse skin. In keratinocytes, DLX3 exhibited a biphasic response, with early induction followed by progressive depletion after prolonged exposure. DLX3 deficiency increased susceptibility to osimertinib-induced apoptosis, whereas osimertinib-induced DLX3 depletion was associated with accelerated protein turnover and lysosome-related alterations.Osimertinib-induced DLX3 depletion was accompanied by increased STAT3 phosphorylation and alterations in autophagy–lysosome-associated markers. Cryptotanshinone suppressed STAT3 phosphorylation, restored DLX3 protein abundance, and reduced osimertinib-induced apoptosis, DNA damage, and inflammatory responses. Loss of DLX3 weakened the protective effects of cryptotanshinone. In mice, cryptotanshinone alleviated osimertinib-induced skin lesions, epidermal injury, apoptosis, mast cell infiltration, and systemic inflammation.Collectively, these findings indicate that progressive DLX3 depletion is associated with STAT3 activation and autophagy–lysosome-related alterations during osimertinib-induced cutaneous toxicity and suggest that preservation of DLX3 protein homeostasis may represent a strategy for mitigating drug-induced skin injury.