The natural product Honokiol exhibits robust antitumor activity against a range of cancers, and it has also received approval to undergo phase I clinical trial testing. We confrmed that honokiol can promote the apoptotic death of tumor cells through cell experiments. Then siRNA constructs specific for PIAS3, PIAS3 overexpression plasmid and the mutation of the STAT3 Tyr705 residue were used to confirm the mechanism of Honokiol-induced apoptosis. Finally, we confrmed that honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation through the in vivo and in vitro experiments. Honokiol was ultimately found to reduce tumor cell viability by promoting apoptosis through a mechanism dependent on the ability of Honokiol to promote PIAS3 upregulation and the selective inhibition of p-STAT3 (Tyr705) without affecting p-STAT3 (Ser727) or p-STAT1 (Tyr701) levels. PIAS3 knockdown and overexpression in tumor cells altered STAT3 activation and associated DNA binding activity through the control of Tyr705 phosphorylation via PIAS3-STAT3 complex formation, ultimately shaping Honokiol-induced tumor cell apoptosis. Honokiol was also confirmed to significantly prolong the survival of mice bearing xenograft tumors in a PIAS3-dependent fashion. Together, these findings highlight a novel pathway through which Honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation and promoting the apoptotic death of tumor cells.

天然产物和厚朴酚对多种癌症表现出强大的抗肿瘤活性，并且已获准进行一期临床试验。我们通过细胞实验证实和厚朴酚可以促进肿瘤细胞的凋亡。然后使用PIAS3特异性的siRNA构建体、PIAS3过表达质粒和STAT3 Tyr705残基的突变来证实和厚朴酚诱导细胞凋亡的机制。最后，我们通过体内外实验证实和厚朴酚可以促进PIAS3上调，进而抑制STAT3 Tyr705磷酸化。最终发现和厚朴酚通过促进细胞凋亡来降低肿瘤细胞活力，其机制依赖于和厚朴酚促进 PIAS3 上调和选择性抑制 p-STAT3 (Tyr705) 的能力，而不影响 p-STAT3 (Ser727) 或 p-STAT1 (Tyr701) ）水平。肿瘤细胞中 PIAS3 敲除和过度表达通过 PIAS3-STAT3 复合物形成控制 Tyr705 磷酸化，改变 STAT3 激活和相关 DNA 结合活性，最终形成和厚朴诱导的肿瘤细胞凋亡。和厚朴酚也被证实能够以 PIAS3 依赖性方式显着延长携带异种移植肿瘤的小鼠的存活时间。总之，这些发现凸显了厚厚朴酚可以促进 PIAS3 上调，进而抑制 STAT3 Tyr705 磷酸化并促进肿瘤细胞凋亡的新途径。