在“最难治疗”的肿瘤中，为么「铁死亡」如此要紧？这篇31分的科研道尽了！
<span style="color: black;"><span style="color: black;">做为</span>最难治疗的乳腺癌亚型，<strong style="color: blue;">三阴乳腺癌（TNBC）</strong><span style="color: black;">迄今</span>仍缺乏有效的治疗<span style="color: black;">干涉</span>手段。TNBC是一类<span style="color: black;">饱含</span>铁以及脂质的肿瘤，<span style="color: black;">因此</span><strong style="color: blue;">“诱导铁死亡”</strong><span style="color: black;">作为</span>值得探索的治疗策略。但鉴于铁死亡是一个逐步的过程，且受到多种代谢途径的调节，TNBC中铁死亡的清晰图景仍未被揭示。</span><span style="color: black;">最难治疗的乳腺癌亚型<strong style="color: blue;">「TNBC」</strong>与国自然热门<span style="color: black;">科研</span>对象<strong style="color: blue;">「铁死亡」</strong><span style="color: black;">怎样</span>构建联系？<span style="color: black;">怎样</span>着手<span style="color: black;">科研</span>？</span><span style="color: black;">梅斯<span style="color: black;">博主</span>就这篇<span style="color: black;">发布</span>于<strong style="color: blue;">《Cell Metabolism》</strong>（31.373分）的“</span><span style="color: black;">Ferroptosis heterogeneity intriple-negative breast cancer reveals an innovative immunotherapy combination
strategy</span><span style="color: black;">”</span><span style="color: black;"></span><span style="color: black;"><span style="color: black;">文案</span>入手，来为<span style="color: black;">大众</span>介绍一下。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshO1iaz9ZZ0kShhf6uMfFxevSn4kl15HnbicibhBoWzeyicPjFuz5lYIptdyg/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">1、</span><span style="color: black;">科研</span>内容与思路</span></strong></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;">1、探究TNBC亚型中铁死亡<span style="color: black;">关联</span>特征的异质性</span></strong></span><span style="color: black;">作者采用多组学TNBC数据集（n=465）来<span style="color: black;">评定</span>铁死亡特征，并探索精确靶向TNBC铁死亡的潜在机会。</span><span style="color: black;">结果<span style="color: black;">发掘</span>，TNBC亚型显示出<span style="color: black;">显著</span>的铁死亡<span style="color: black;">关联</span>特征——TNBC亚型LAR肿瘤的特征在于几种铁死亡<span style="color: black;">关联</span>途径的上调和OxPE的富集，这<span style="color: black;">寓意</span>着铁死亡的潜在脆弱性。</span><span style="color: black;"><span style="color: black;">同期</span>，LAR肿瘤<span style="color: black;">怎样</span>灭活铁死亡程序以逃避细胞死亡尚不清楚。这<span style="color: black;">亦</span><span style="color: black;">促进</span><span style="color: black;">科研</span>者关注LAR肿瘤中铁死亡的调节机制，以探索治疗<span style="color: black;">方法</span>。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshONPu6k1FEoEVgxSNtsmXRw6nVm1lmHSkdc20VHjEjpp6XTJ39v3Zn1Q/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">科研</span>思路：</span></strong><span style="color: black;"><span style="color: black;">按照</span>之前的<span style="color: black;">科研</span>，<span style="color: black;">科研</span>者猜想TNBC与铁死亡之间存在联系，<span style="color: black;">然则</span><span style="color: black;">详细</span>是何种联系还有待挖掘。于是，作者基于铁死亡与细胞代谢的联系采用多组学分析，<span style="color: black;">科研</span>TNBC四种亚型与铁死亡的关系，<span style="color: black;">最后</span>定位到TNBC亚型之一LAR肿瘤。</span></span><strong style="color: blue;"><span style="color: black;">2、谷胱甘肽代谢<span style="color: black;">针对</span><span style="color: black;">控制</span>LAR肿瘤中的铁死亡至关<span style="color: black;">要紧</span></span></strong><span style="color: black;">作者采用代谢组学和转录组学数据来探索<span style="color: black;">控制</span>LAR肿瘤铁死亡的最<span style="color: black;">重点</span>途径，<span style="color: black;">发掘</span>LAR肿瘤中最<span style="color: black;">显著</span>的铁死亡<span style="color: black;">控制</span>途径与谷胱甘肽（GSH）<span style="color: black;">相关</span>。<span style="color: black;">经过</span>比较GSH循环中核心代谢物的丰度<span style="color: black;">发掘</span>GSH<span style="color: black;">关联</span>代谢物在LAR肿瘤中<span style="color: black;">明显</span>富集。</span><span style="color: black;">在TNBC细胞系中，<span style="color: black;">亦</span>证实了LAR亚型中谷胱甘肽与氧化谷胱甘肽(GSSG)的较高比率。作者还比较了转录组学中LAR和非LAR肿瘤之间的铁死亡<span style="color: black;">控制</span>途径，进一步证明了GSH代谢是LAR亚型中必不可少的铁死亡<span style="color: black;">控制</span>途径。</span><span style="color: black;">在GSH通路的所有代谢基因中，GPX4将LAR肿瘤与非LAR对应物区<span style="color: black;">掰开</span>来。于是，作者采用测序进一步验证GPX4的潜在<span style="color: black;">重要</span><span style="color: black;">功效</span>以及肿瘤细胞对铁死亡的高易感性，<span style="color: black;">发掘</span>癌症上皮细胞表达高水平的GSH代谢基因，并在铁死亡方面与其他细胞区<span style="color: black;">掰开</span>来。</span><span style="color: black;">在这种<span style="color: black;">状况</span>下，GPX4<span style="color: black;">控制</span>剂<span style="color: black;">一般</span>可能靶向肿瘤细胞，并且对免疫细胞的抗肿瘤<span style="color: black;">功效</span>的<span style="color: black;">害处</span>较小。</span><span style="color: black;">这些数据<span style="color: black;">显示</span>，GPX4是GSH代谢的潜在决定<span style="color: black;">原因</span>，可<span style="color: black;">控制</span>LAR肿瘤中的铁死亡。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshOzicZBrAlQn6NKptBIOuIJhicKwkVeUUKRUmicicNqxaVnTCfCNbxFKe91w/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">科研</span>思路：</span></strong><span style="color: black;">定位到主角LAR肿瘤对铁死亡最为<span style="color: black;">敏锐</span>后，进一步探究<span style="color: black;">控制</span>LAR肿瘤铁死亡的最<span style="color: black;">重点</span>途径，<span style="color: black;">发掘</span>谷胱甘肽的<span style="color: black;">要紧</span><span style="color: black;">功效</span>后，从基因层面进行挖掘，<span style="color: black;">最后</span>发现GPX4。<span style="color: black;">因此</span>作者得出结论：GPX4是GSH代谢的潜在决定<span style="color: black;">原因</span>，可<span style="color: black;">控制</span>LAR肿瘤中的铁死亡。</span></span><strong style="color: blue;"><span style="color: black;">3、对多种铁死亡诱导剂的独特<span style="color: black;">敏锐</span>性凸显了GPX4在LAR肿瘤中的<span style="color: black;">要紧</span>性</span></strong><span style="color: black;"><span style="color: black;">科研</span>者进一步探索了针对LAR肿瘤铁死亡的最佳治疗策略。<span style="color: black;">首要</span>，组装了一组铁死亡诱导剂，<span style="color: black;">包含</span>erastin、PX-12、FIN-56、RSL3和ML162（GPX4<span style="color: black;">控制</span>剂），以<span style="color: black;">评定</span>每种化合物在<span style="color: black;">起步</span>LAR，非LAR和非TNBC细胞系中的铁死亡的功效。</span><span style="color: black;">结果<span style="color: black;">发掘</span>，在IC50<span style="color: black;">实验</span>中，证明了GPX4在LAR肿瘤铁死亡稳态中的<span style="color: black;">要紧</span>性，细胞克隆形成实验进一步确认，LAR肿瘤细胞对GPX4<span style="color: black;">控制</span>剂的灵敏度最高。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshOH1HKt8szK7tXoMt0fkNL0O7wb9A4GT3iaMzeud1dicUNvxf1icUR8ucgQ/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">科研</span>思路：</span></strong><span style="color: black;">采用多种铁死亡诱导剂来验证<span style="color: black;">以上</span>所得结论——GPX4可<span style="color: black;">控制</span>LAR肿瘤中的铁死亡。层层递进，<span style="color: black;">持续</span>深挖，<span style="color: black;">持续</span>验证，为后续实验奠定<span style="color: black;">基本</span>。</span></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;">4、AR是LAR肿瘤中GPX4表达的<span style="color: black;">重要</span>调节因子</span></strong></span><span style="color: black;">为了探索<span style="color: black;">引起</span>LAR肿瘤中GPX4表达<span style="color: black;">增多</span>的潜在上游机制，作者采用多组学分析<span style="color: black;">发掘</span>LAR的特异性改变与GPX4的表达量呈<span style="color: black;">明显</span><span style="color: black;">关联</span>性。</span><span style="color: black;"><span style="color: black;">经过</span>一系列的验证以及<span style="color: black;">控制</span>剂<span style="color: black;">运用</span>对比，<span style="color: black;">最后</span><span style="color: black;">发掘</span>HEK293T细胞中的AR过表达<span style="color: black;">引起</span>mRNA和蛋白质水平的GPX4表达<span style="color: black;">增多</span>，而敲低AR表达<span style="color: black;">引起</span>MDA-MB-453和MFM-223细胞中mRNA和蛋白质水平的GPX4表达降低，<span style="color: black;">知道</span>了AR为LAR肿瘤中GPX4表达的<span style="color: black;">重要</span>调节因子。</span><span style="color: black;">接下来探讨了AR调节GPX4的机制——作者<span style="color: black;">发掘</span>AR在转录水平上调了GPX4表达。<span style="color: black;">因此呢</span>，作者采用转录测定和染色质免疫沉淀（ChIP）测定<span style="color: black;">知道</span>了AR与MDA-MB-453和MFM-223细胞中GPX4基因上游的-2500
bp--2000 bp的区域相互<span style="color: black;">功效</span>。</span><span style="color: black;"><span style="color: black;">另外</span>，作者还探讨了AR<span style="color: black;">可否</span>将GPX4表达<span style="color: black;">做为</span>第二信使来调控。</span><span style="color: black;"><span style="color: black;">最后</span>得出结论：</span><span style="color: black;">AR与GPX4<span style="color: black;">起步</span>子结合并驱动其表达。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshO1Okjep0PKIxTzUU5oAZTx9RAW7OCg0dNu2Mjh2NDGy4YkvlMhFobYw/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">科研</span>思路：</span></strong><span style="color: black;"><span style="color: black;">知道</span>GPX4对LAR肿瘤的<span style="color: black;">功效</span>后，接下来便是<span style="color: black;">知道</span>其<span style="color: black;">功效</span>机制，作者<span style="color: black;">首要</span><span style="color: black;">发掘</span>GXP4表达差异与LAR特异性表达<span style="color: black;">关联</span>，之后探索了<span style="color: black;">引起</span>GXP4表达差异的上游机制，<span style="color: black;">发掘</span>AR，后又探索AR调节GXP4的机制。</span></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;">5、AR在调节铁死亡方面的双重<span style="color: black;">功效</span><span style="color: black;">显示</span>，<span style="color: black;">针对</span>LAR TNBC<span style="color: black;">病人</span>，靶向GPX4是比靶向AR更好的策略</span></strong></span><span style="color: black;"><span style="color: black;">思虑</span>到GPX4是LAR肿瘤铁死亡的潜在<span style="color: black;">控制</span>因子，AR驱动GPX4的表达，作者想<span style="color: black;">晓得</span>AR在LAR肿瘤细胞系铁死亡中的<span style="color: black;">功效</span>。</span><span style="color: black;">用比卡鲁胺（靶向细胞核中的雄激素<span style="color: black;">关联</span>元素）、达罗他胺（靶向AR核易位）、恩杂鲁胺（靶向AR核易位）和GPX4<span style="color: black;">控制</span>剂处理MDA-MB-453和MFM-223细胞并分析铁死亡<span style="color: black;">状况</span>，<span style="color: black;">发掘</span>GPX4<span style="color: black;">控制</span>剂而不是AR<span style="color: black;">控制</span>剂扩大了脂质过氧化水平并<span style="color: black;">加强</span>了铁死亡。</span><span style="color: black;">于是，进一步探讨AR<span style="color: black;">控制</span>剂促进铁死亡的可能机制。</span><span style="color: black;">先前的<span style="color: black;">科研</span><span style="color: black;">显示</span>，AR<span style="color: black;">能够</span><span style="color: black;">经过</span>下调2,4-二烯酰基辅酶a还原酶(DECR1)(一种直接雄激素<span style="color: black;">控制</span>基因)促进FA代谢，尤其是PUFA<span style="color: black;">累积</span>。<span style="color: black;">另外</span>，还<span style="color: black;">发掘</span>添加GPX4<span style="color: black;">控制</span>剂后，脂质过氧化的生物标志物MDA上调。</span><span style="color: black;">这些数据证明了AR在铁死亡中的多元<span style="color: black;">功效</span>。一方面，AR可能促进PUFA生物合成以支持铁死亡；另一方面，AR可能会上调GPX4的表达以清除铁死亡过程中的脂质过氧化。</span><span style="color: black;"><span style="color: black;">因此呢</span>，<span style="color: black;">控制</span>GPX4，而不是<span style="color: black;">控制</span>AR，是LAR肿瘤<span style="color: black;">病人</span>诱导铁死亡的最佳<span style="color: black;">办法</span>。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshOibVVcfIfaQfq7yUicoHRe2PsEnuFVZxUyEQ1Aia01S1ILDKXxyCujwrAQ/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">科研</span>思路：</span></strong><span style="color: black;"><span style="color: black;">知道</span>了整个<span style="color: black;">功效</span>途径后，接下来便是将其与临床结合，<span style="color: black;">加强</span><span style="color: black;">科研</span>格局，于是作者将目光转移到免疫<span style="color: black;">控制</span>剂层面，探究AR<span style="color: black;">控制</span>或GXP4<span style="color: black;">控制</span><span style="color: black;">针对</span><span style="color: black;">病人</span>肿瘤铁死亡的调节<span style="color: black;">功效</span>。在<span style="color: black;">发掘</span>AR<span style="color: black;">控制</span><span style="color: black;">不睬</span>想的<span style="color: black;">状况</span>下，作者还深挖了<span style="color: black;">为何</span><span style="color: black;">不睬</span>想的<span style="color: black;">原由</span>。</span></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;">6、GPX4<span style="color: black;">控制</span>剂减少肿瘤生长并重新编程<span style="color: black;">身体</span>肿瘤微环境</span></strong></span><span style="color: black;">作者进行了动物实验。</span><span style="color: black;"><span style="color: black;">首要</span>，<span style="color: black;">评定</span>GPX4<span style="color: black;">控制</span>剂在<span style="color: black;">身体</span>表达AR的TNBC肿瘤中的抗癌<span style="color: black;">功效</span>，<span style="color: black;">发掘</span>敲低GPX4表达或添加GPX4<span style="color: black;">控制</span>剂可<span style="color: black;">明显</span>诱导肿瘤中的铁死亡，但不诱导细胞凋亡。</span><span style="color: black;"><span style="color: black;">另外</span>，作者还<span style="color: black;">科研</span>了GPX4敲低或GPX4<span style="color: black;">控制</span>剂对肿瘤微环境的影响，<span style="color: black;">发掘</span><span style="color: black;">控制</span>GPX4有效地<span style="color: black;">引起</span>PTGS2、MDA和4-HNE(<span style="color: black;">药品</span>诱导的铁死亡的生物标志物)的<span style="color: black;">上升</span>，以及CD3e细胞、CD4细胞、CD8细胞和CD86细胞的聚集，并减少CD206细胞的数量。<span style="color: black;">关联</span>性分析<span style="color: black;">显示</span>，GSH代谢与CD8T细胞和M1巨噬细胞比例呈负<span style="color: black;">关联</span>，而与M2巨噬细胞和静息肥大细胞比例呈正<span style="color: black;">关联</span>。</span><span style="color: black;">这些数据<span style="color: black;">显示</span>，<span style="color: black;">控制</span>LAR肿瘤中GPX4表达<span style="color: black;">明显</span>促进铁死亡，减少肿瘤生长，并触发肿瘤微环境<span style="color: black;">得到</span>炎症表型。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshOhfaicGthEibf2UCI8LQrbQJlGCYvqybv6k7d25qN2x09R0Np8usiczQ5Q/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;">研究思路：</span></strong><span style="color: black;">之前的<span style="color: black;">科研</span>以及机制分析都是在细胞层面构建的，<span style="color: black;">那样</span>在动物实验中<span style="color: black;">可否</span>会取得相应的结论。为此，作者采用了两种动物模型，一种是LAR肿瘤模型，一种是免疫冷肿瘤模型，<span style="color: black;">最后</span>得到了相同的结论，实验严谨。</span></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;">7、GPX4<span style="color: black;">控制</span>剂与ICB联合<span style="color: black;">运用</span>对生物学特征类似于LAR的肿瘤有效</span></strong></span><span style="color: black;">为了测试GPX4<span style="color: black;">控制</span>剂和免疫疗法<span style="color: black;">可否</span>发挥协同<span style="color: black;">功效</span>，构建LAR肿瘤模型小鼠并用GPX4<span style="color: black;">控制</span>剂或DMSO加PD-1阻断治疗小鼠。</span><span style="color: black;">结果<span style="color: black;">发掘</span>，与单药治疗相比，GPX4<span style="color: black;">控制</span>剂和抗PD-1抗体联合治疗可<span style="color: black;">明显</span><span style="color: black;">控制</span>肿瘤生长，流式结果<span style="color: black;">暗示</span>，联合治疗诱导<span style="color: black;">剧烈</span>的免疫反应，且PRF1+
CD8T细胞/GZMB+CD8+T细胞的比率大幅<span style="color: black;">上升</span>。此外，联合治疗破坏了不同分支点的GSH代谢。病理结果<span style="color: black;">表示</span>了联合治疗<span style="color: black;">运用</span>的安全性。</span><span style="color: black;">接下来，作者<span style="color: black;">科研</span>了LAR亚型对GSH代谢的<span style="color: black;">控制</span><span style="color: black;">功效</span><span style="color: black;">可否</span>与两个队列中<span style="color: black;">病人</span>对ICB的临床反应<span style="color: black;">关联</span>。</span><span style="color: black;">结果<span style="color: black;">发掘</span>，AR高表达的TNBC<span style="color: black;">病人</span>表现出<span style="color: black;">加强</span>的铁代谢，且不饱和脂肪酸代谢和GSH代谢活力<span style="color: black;">提升</span>。其中，GSH新陈代谢和肿瘤炎症、STAT1、IFN-γ、PD-1表达量和M1型巨噬细胞的比例呈负<span style="color: black;">关联</span>，但与M2型巨噬细胞的比例呈正<span style="color: black;">关联</span>。Er2GSH代谢与GXP4息息<span style="color: black;">关联</span>，这<span style="color: black;">显示</span>了GXP4在LAR肿瘤中的<span style="color: black;">要紧</span>性。</span><span style="color: black;">由此可得：GPX4<span style="color: black;">控制</span>剂与ICB的组合是生物学特征方面类似于LAR的肿瘤的最佳治疗<span style="color: black;">办法</span>。</span><img src="https://mmbiz.qpic.cn/mmbiz_jpg/eNCIyl9QqIx91u34I6IibxGZ5WSYWjshO0xGb58VBHkRtNHlXkWWh1VgbjTNLZyh1Qv3mzAOycWEh7AUgv1fh7Q/640?wx_fmt=jpeg&tp=webp&wxfrom=5&wx_lazy=1&wx_co=1" style="width: 50%; margin-bottom: 20px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">科研</span>思路：</span></strong><span style="color: black;">细胞+动物都得到了证实，那这一<span style="color: black;">发掘</span><span style="color: black;">可否</span><span style="color: black;">能够</span><span style="color: black;">针对</span>临床有<span style="color: black;">帮忙</span>呢？作者将目光瞄准到免疫治疗，采用<span style="color: black;">控制</span>剂+免疫治疗<span style="color: black;">药品</span>的<span style="color: black;">办法</span>开展动物实验，<span style="color: black;">最后</span>证实了猜想，并结合临床样本测序，进一步证实猜想，升华<span style="color: black;">科研</span>内容。</span></span><span style="color: black;"><strong style="color: blue;"><span style="color: black;"><span style="color: black;">2、</span>小结</span></strong></span><span style="color: black;">此篇<span style="color: black;">文案</span><span style="color: black;">科研</span>思路层层递进——先是采用多组学测序探究TNBC亚型跟铁死亡关系；<span style="color: black;">知道</span>主角后，从细胞<span style="color: black;">方向</span>出发，将整条<span style="color: black;">功效</span>途径明确；之后发展到动物实验，验证所<span style="color: black;">发掘</span>的<span style="color: black;">功效</span>途径；<span style="color: black;">最后</span>将目光移到临床治疗，<span style="color: black;">显示</span>后续可能<span style="color: black;">能够</span>采用GXP4<span style="color: black;">控制</span>剂联合免疫治疗来治疗TNC亚型LAR肿瘤。其<span style="color: black;">科研</span>思路值得借鉴！</span>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">参考文献：</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">Yang F, Xiao Y, Ding JH, et al. Ferroptosis
heterogeneity in triple-negative breast cancer reveals an innovative
immunotherapy combination strategy. Cell Metab. 2023;35(1):84-100.e8.</span></p><span style="color: black;">撰写：MIE</span>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">编辑：小饼干</span></p>
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