Protective effects of BTK inhibition by acalabrutinib on cisplatin-induced renal and testicular injury in mice: Modulation of mTOR/AMPK, NLRP3/GSDMD-N, and apoptotic pathways.

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-02-11 DOI:10.1016/j.intimp.2025.114256

Sara H. Hazem, Karim M. Saad, Mahmoud M. Samaha

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Abstract

Background

Cisplatin-induced nephrotoxicity and testicular injury pose significant challenges during chemotherapy.

Aim

The current study evaluates the efficacy of acalabrutinib (ACB), a Bruton’s tyrosine kinase inhibitor, in mitigating cisplatin-induced damage in renal and testicular tissues in mice.

Methods

Testicular and renal toxicity was induced by a single I.P. injection of cisplatin (25 mg/kg). Mice were randomized into four groups: Normal (treated with vehicle), Cis (cisplatin + vehicle), Cis + ACB (6 mg/kg), and Cis + ACB (12 mg/kg). ACB was administered orally for three consecutive days, starting at Day 0 (1 h before single I.P. injection of cisplatin) and continued for Day 1 and Day 2.

Results

ACB treatment (6 mg/kg and 12 mg/kg) significantly improved renal function by reducing serum creatinine, BUN, and KIM-1 levels, while also attenuating inflammation and apoptosis, as evidenced by decreased NLRP3, CD68, and caspase-3 expression. Additionally, it mitigated molecular damage by downregulating mTOR, AMPK, and GSDMD-N. In testicular tissues, ACB preserved structure, restored spermatogenesis, and improved sperm viability and testosterone levels. The protective effects were associated with reduced inflammation, apoptosis, and pyroptosis, indicated by lower levels of cathepsin L, NLRP3, and GSDMD-N.

Conclusions

These findings suggest that ACB offers a promising therapeutic approach to reduce the adverse effects of cisplatin, potentially enhancing the overall efficacy and safety of chemotherapy regimens.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.